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Inner core biosynthesis of lipooligosaccharide (LOS) in Neisseria meningitidis serogroup B: identification and role in LOS assembly of the alpha1,2 N-acetylglucosamine transferase (RfaK).
Kahler, C M
Carlson, R W
Rahman, M M
Martin, L E
Stephens, D S
Journal of Bacteriology
A lipooligosaccharide (LOS) mutant of Neisseria meningitidis serogroup B strain NMB (immunotype L3,7,9) was identified in a Tn916 (tetM) mutant bank by loss of reactivity with monoclonal antibody 3F11, which recognizes the terminal Galbeta1-->4GlcNAc epitope in the lacto-N-neotetraose moiety of the wild-type LOS structure. The mutant, designated 559, was found to express a truncated LOS of 3.0 kDa. Southern and PCR analyses demonstrated that there was a single intact Tn916 insertion (class I) in the mutant 559 chromosome. Linkage of the LOS phenotype and the Tn916 insertion was confirmed by transformation of the wild-type parent. Nucleotide sequence analysis of the region surrounding the transposition site revealed a 1,065-bp open reading frame (ORF). A homology search of the GenBank/EMBL database revealed that the amino acid sequence of this ORF had 46.8% similarity and 21.2% identity with the alpha1,2 N-acetylglucosamine transferase (RfaK) from Salmonella typhimurium. Glycosyl composition and linkage analysis of the LOS produced by mutant 559 revealed that the lacto-N-neotetraose group which is attached to heptose I (HepI) and the N-acetylglucosamine and glucose residues that are attached to HepII in the inner core of the parental LOS were absent. These analyses also showed that the HepII residue in both the parent and the mutant LOS molecules was phosphorylated, presumably by a phosphoethanolamine substituent. The insertion of nonpolar and polar antibiotic resistance cartridges into the parental rfaK gene resulted in the expression of LOS with the same mobility as that produced by mutant 559. This result indicated that the inability to add the lacto-N-neotetraose group to the 559 LOS is not due to a polar effect on a gene(s) downstream of rfaK. Our data indicate that we have identified the meningococcal alpha1,2 N-acetylglucosamine transferase responsible for the addition of N-acetylglucosamine to HepII. We propose that the lack of alpha-chain extension from HepI in the LOS of mutant 559 may be due to structural constraints imposed by the incomplete biosynthesis of the LOS inner core.
Related Articles
Immunotype epitopes of Neisseria meningitidis lipooligosaccharide types 1 through 8.
Tsai, C M
Mocca, L F
Frasch, C E
Infection and Immunity
Lipooligosaccharides (LOS) of the eight immunotypes found in serogroup B Neisseria meningitidis were purified from their prototype strains grown in tryptic soy broth. Rabbit antisera to these LOS were prepared. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis followed by silver staining revealed that most of the LOS antigens contained two major components; the larger components had apparent molecular weights (Mrs) in the range of 4,800 +/- 300, and the smaller components had an apparent Mr of 4,300. Immunoblot analysis showed that the larger major component of an LOS, in general, was much more immunogenic because the rabbits produced antibodies exclusively or primarily to this component even though the LOS immunogen contained both large and small major components. Antibodies to the smaller 4,300-Mr components were infrequently observed but, when present, were cross-reactive with the same-size components of all heterologous LOS. Hence, the immunotype epitopes reside in the larger major components of all immunotypes except type 5, in which a smaller major component having an apparent Mr of 4,400 carries the epitope. Rabbit antisera to types 1, 5, and 6 were immunotype specific. Antisera to other types had cross-reactivities with some heterologous LOS, and the larger components, but not the 4,300-Mr components, of the LOS were primarily responsible for the cross-reactivities. This finding suggests that the larger components of cross-reactive LOS have a similar structure in addition to their type-specific sugar moieties. The LOS of N. meningitidis M986, a strain used for the production of a serotype 2a vaccine, was found to contain the immunotype 7 epitope.
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Preparation, characterization, and immunogenicity of meningococcal lipooligosaccharide-derived oligosaccharide-protein conjugates.
Gu, X X
Tsai, C M
Infection and Immunity
A method was developed for coupling carboxylic acid-containing oligosaccharides (OS) to proteins. An OS was isolated from Neisseria meningitidis group A strain A1 lipooligosaccharide (LOS). This LOS has no human glycolipid-like lacto-N-neotetraose structure and contains multiple immunotypes, including L8, found in group B and C strains. The carboxylic acid at 2-keto-3-deoxyoctulosonic acid of the OS was linked through adipic acid dihydrazide to tetanus toxoid. The molar ratio of the OS to tetanus toxoid in three conjugates ranged from 11:1 to 19:1. The antigenicity of the OS was conserved in these conjugates, as measured by an enzyme-linked immunosorbent assay (ELISA) and an inhibition ELISA with polyclonal and monoclonal antibodies to A1 LOS. These conjugates induced immunoglobulin G antibodies to A1 LOS in mice and rabbits. The immunogenicity of the conjugates in rabbits was enhanced by use of monophosphoryl lipid A plus trehalose dimycolate as an adjuvant. The resulting rabbit antisera cross-reacted with most of 12 prototype LOSs and with LOSs from two group B disease strains, 44/76 and BB431, in an ELISA and in Western blotting (immunoblotting), which revealed a 3.6-kDa reactive band in these LOSs. The rabbit antisera showed bactericidal activity against homologous strain A1 and heterologous strains 44/76 and BB431. These results indicate that conjugates derived from A1 LOS can induce antibodies against many LOS immunotypes from different organism serogroups, including group B. OS-protein conjugates derived from meningococcal LOSs may therefore be candidate vaccines to prevent meningitis caused by meningococci.
Related Articles
Serological diversity and chemical structures of Campylobacter jejuni low-molecular-weight lipopolysaccharides.
Aspinall, G O
McDonald, A G
Raju, T S
Pang, H
Mills, S D
Kurjanczyk, L A
Penner, J L
Journal of Bacteriology
Low-Mr lipopolysaccharides (LPS) of Campylobacter jejuni reference strains for serotypes O:1, O:4, O:23, and O:36 were examined through the liberation of core oligosaccharides by mild acid cleavage of the ketosidic linkage of 3-deoxy-D-manno-2-octulosonic acid residues to the lipid A moiety. The liberated oligosaccharides were examined for chemical structure by compositional analysis and methylated linkage analysis in conjunction with fast atom bombardment-mass spectrometry of permethylated oligosaccharide derivatives. The results showed (i) that the LPS contained short oligosaccharide chains of branched nonrepetitive structure, to many of which N-acetylneuraminic acid residues remained attached by 2----3 linkages to 4-linked D-galactose residues in the core structure; (ii) that serotypical differences, which are not readily defined through qualitatively similar compositions, are clearly reflected in variations in linkage types and sequences of sugar residues in the outer core attached to an inner region of invariable structure; but (iii) that the presence or absence of NeuAc residues does not appear to be a basis for serotypical differences. The results also showed that oligosaccharide chains from LPS of serotypes O:1 and O:4 are distinctly different and are distinct again from those of the cross-reacting serotypes O:23 and O:36, between whose core oligosaccharide chains no differences were found. It is concluded that the structurally variable low-Mr LPS from C. jejuni show greater similarities to the lipooligosaccharides from Neisseria spp. than to the highly conserved core regions of Salmonella species. Those strains (serotypes O:23 and O:36) which also furnish high-Mr LPS are unique among gram-negative bacteria in possessing both low-Mr molecules of the Neisseria lipooligosaccharide type and high-Mr LPS of the Salmonella smooth type.
Related Articles
Production and characterization of monoclonal antibodies to type 8 lipooligosaccharide of Neisseria meningitidis.
Gu, X X
Tsai, C M
Karpas, A B
Journal of Clinical Microbiology
Eight monoclonal antibodies (MAbs) to lipooligosaccharides (LOSs) of Neisseria meningitidis were produced by immunizing mice with purified LOS from group A meningococcal strain A1. The specificities of the MAbs were examined by enzyme-linked immunosorbent assay (ELISA), immunodot assay, and ELISA inhibition by using the homologous A1 LOS, 12 immunotype LOSs of N. meningitidis (L1 through L12), and LOSs or lipopolysaccharides from other gram-negative bacteria. Two of the MAbs, 4385G7 (immunoglobulin G2b [IgG2b]) and 4387A5 (IgG2a), had the strongest reactivities with the homologous A1 LOS, moderate reactivities with the M978 (L8) LOS, but no reactivity with other LOSs. The other six MAbs (4 IgM and 2 IgG3) reacted with the A1 LOS and with several or many of the 12 LOSs. ELISA inhibition at 50% showed that the inhibitory activities of the LOSs from strains A1 and BB431 (a group B strain) to the specific MAb 4387A5 were about 10 to 20 times greater than that of the M978 (L8) LOS. When compared with MAb 2-1-L8 (L8) by Western blot (immunoblot) analysis and ELISA inhibition, the two specific MAbs recognized a different epitope in the 3.6-kDa LOSs of strains A1 and BB431. We propose that the new epitope is L8a, since the MAbs also reacted with the M978 (L8) LOS. The expression of the L8a epitope in the A1 LOS requires a few monosaccharide residues in its oligosaccharide moiety, and the fatty acid residues in its lipid A moiety also play a role. In a whole-cell ELISA, the two specific MAbs bound specifically to the homologous strain A1 and the L8 prototype strain M978 but not to any other LOS prototype strains. These results suggest that the two specific MAbs can be used for LOS typing of N. meningitidis.
Related Articles
Conservation and Accessibility of an Inner Core Lipopolysaccharide Epitope of Neisseria meningitidis
Plested, Joyce S.
Makepeace, Katherine
Jennings, Michael P.
Gidney, Margaret Anne J.
Lacelle, Suzanne
Brisson, J.-R.
Cox, Andrew D.
Martin, Adele
Bird, A. Graham
Tang, Christoph M.
Mackinnon, Fiona M.
Richards, James C.
Moxon, E. Richard
Infection and Immunity
We investigated the conservation and antibody accessibility of inner core epitopes of Neisseria meningitidis lipopolysaccharide (LPS) because of their potential as vaccine candidates. An immunoglobulin G3 murine monoclonal antibody (MAb), designated MAb B5, was obtained by immunizing mice with a galE mutant of N. meningitidis H44/76 (B.15.P1.7,16 immunotype L3). We have shown that MAb B5 can bind to the core LPS of wild-type encapsulated MC58 (B.15.P1.7,16 immunotype L3) organisms in vitro and ex vivo. An inner core structure recognized by MAb B5 is conserved and accessible in 26 of 34 (76%) of group B and 78 of 112 (70%) of groups A, C, W, X, Y, and Z strains. N. meningitidis strains which possess this epitope are immunotypes in which phosphoethanolamine (PEtn) is linked to the 3-position of the β-chain heptose (HepII) of the inner core. In contrast, N. meningitidis strains lacking reactivity with MAb B5 have an alternative core structure in which PEtn is linked to an exocyclic position (i.e., position 6 or 7) of HepII (immunotypes L2, L4, and L6) or is absent (immunotype L5). We conclude that MAb B5 defines one or more of the major inner core glycoforms of N. meningitidis LPS. These findings support the possibility that immunogens capable of eliciting functional antibodies specific to inner core structures could be the basis of a vaccine against invasive infections caused by N. meningitidis.
Related Articles
Influence of the Length of the Lipooligosaccharide α Chain on Its Sialylation in Neisseria meningitidis
Tsai, Chao-Ming
Kao, George
Zhu, Peixuan
Infection and Immunity
The sialylation of lipooligosaccharide (LOS) in Neisseria meningitidis plays a role in the resistance of the organism to killing by normal human serum. The length of the α chain extending out from the heptose I [Hep (I)] moiety of LOS influenced sialylation of N. meningitidis LOS in vitro and in vivo. The α chain required a terminal Gal and a trisaccharide or longer oligosaccharide to serve as an acceptor for sialylation. The disaccharide lactose (Galβ1-4Glc) in the α chain of immunotype L8 LOS could not function as an acceptor for the sialyltransferase, probably due to steric hindrance imposed by the neighboring Hep (II) with phosphorylethanolamine and another group attached.
Related Articles
Genotypic and Phenotypic Modifications of Neisseria meningitidis after an Accidental Human Passage
Omer, Hélène
Rose, Graham
Jolley, Keith A.
Frapy, Eric
Zahar, Jean-Ralph
Maiden, Martin C. J.
Bentley, Stephen D.
Tinsley, Colin R.
Nassif, Xavier
Bille, Emmanuelle
PLoS ONE
A scientist in our laboratory was accidentally infected while working with Z5463, a Neisseria meningitidis serogroup A strain. She developed severe symptoms (fever, meningism, purpuric lesions) that fortunately evolved with antibiotic treatment to complete recovery. Pulse-field gel electrophoresis confirmed that the isolate obtained from the blood culture (Z5463BC) was identical to Z5463, more precisely to a fourth subculture of this strain used the week before the contamination (Z5463PI). In order to get some insights into genomic modifications that can occur in vivo, we sequenced these three isolates. All the strains contained a mutated mutS allele and therefore displayed an hypermutator phenotype, consistent with the high number of mutations (SNP, Single Nucleotide Polymorphism) detected in the three strains. By comparing the number of SNP in all three isolates and knowing the number of passages between Z5463 and Z5463PI, we concluded that around 25 bacterial divisions occurred in the human body. As expected, the in vivo passage is responsible for several modifications of phase variable genes. This genomic study has been completed by transcriptomic and phenotypic studies, showing that the blood strain used a different haemoglobin-linked iron receptor (HpuA/B) than the parental strains (HmbR). Different pilin variants were found after the in vivo passage, which expressed different properties of adhesion. Furthermore the deletion of one gene involved in LOS biosynthesis (lgtB) results in Z5463BC expressing a different LOS than the L9 immunotype of Z2491. The in vivo passage, despite the small numbers of divisions, permits the selection of numerous genomic modifications that may account for the high capacity of the strain to disseminate.
Related Articles
Meningococcal Genetic Variation Mechanisms Viewed through Comparative Analysis of Serogroup C Strain FAM18
Bentley, Stephen D
Vernikos, George S
Snyder, Lori A. S
Churcher, Carol
Arrowsmith, Claire
Chillingworth, Tracey
Cronin, Ann
Davis, Paul H
Holroyd, Nancy E
Jagels, Kay
Maddison, Mark
Moule, Sharon
Rabbinowitsch, Ester
Sharp, Sarah
Unwin, Louise
Whitehead, Sally
Quail, Michael A
Achtman, Mark
Barrell, Bart
Saunders, Nigel J
Parkhill, Julian
PLoS Genetics
The bacterium Neisseria meningitidis is commonly found harmlessly colonising the mucosal surfaces of the human nasopharynx. Occasionally strains can invade host tissues causing septicaemia and meningitis, making the bacterium a major cause of morbidity and mortality in both the developed and developing world. The species is known to be diverse in many ways, as a product of its natural transformability and of a range of recombination and mutation-based systems. Previous work on pathogenic Neisseria has identified several mechanisms for the generation of diversity of surface structures, including phase variation based on slippage-like mechanisms and sequence conversion of expressed genes using information from silent loci. Comparison of the genome sequences of two N. meningitidis strains, serogroup B MC58 and serogroup A Z2491, suggested further mechanisms of variation, including C-terminal exchange in specific genes and enhanced localised recombination and variation related to repeat arrays. We have sequenced the genome of N. meningitidis strain FAM18, a representative of the ST-11/ET-37 complex, providing the first genome sequence for the disease-causing serogroup C meningococci; it has 1,976 predicted genes, of which 60 do not have orthologues in the previously sequenced serogroup A or B strains. Through genome comparison with Z2491 and MC58 we have further characterised specific mechanisms of genetic variation in N. meningitidis, describing specialised loci for generation of cell surface protein variants and measuring the association between noncoding repeat arrays and sequence variation in flanking genes. Here we provide a detailed view of novel genetic diversification mechanisms in N. meningitidis. Our analysis provides evidence for the hypothesis that the noncoding repeat arrays in neisserial genomes (neisserial intergenic mosaic elements) provide a crucial mechanism for the generation of surface antigen variants. Such variation will have an impact on the interaction with the host tissues, and understanding these mechanisms is important to aid our understanding of the intimate and complex relationship between the human nasopharynx and the meningococcus.
Author Summary
Human surface tissues, including the skin and gut lining, are host to many different species of bacteria. N. meningitidis is a species of bacteria that is only found in humans where it is able to colonise mucosal surfaces of the nasopharynx (nose and throat). This association is normally harmless and at any one time around 15% of the population are carriers. Some strains of N. meningitidis can cause disease by invading the host tissue leading to septicaemia or meningitis. We aim to gain understanding of the mechanisms by which these bacteria cause disease by studying and comparing genomes from different strains. Here we describe specific genes and associated repetitive DNA sequences that are involved in variation of the bacterial cell surface. The repeat sequences encourage the swapping of genes that code for variant copies of cell surface proteins. The resulting variation of the bacterial cell surface appears to be important in the close interaction between host and bacteria and the potential for disease.
Related Articles
Minimal oligosaccharide structures required for induction of immune responses against meningococcal immunotype L1, L2, and L3,7,9 lipopolysaccharides determined by using synthetic oligosaccharide-protein conjugates.
Verheul, A F
Boons, G J
Van der Marel, G A
Van Boom, J H
Jennings, H J
Snippe, H
Verhoef, J
Hoogerhout, P
Poolman, J T
Infection and Immunity
The 12 types of meningococcal lipopolysaccharide (LPS) (immunotypes) contain immunotype-specific and cross-reactive epitopes situated on the oligosaccharide part of the LPS molecules. To identify useful cross-reactive epitopes and to determine minimal oligosaccharide structures required for the induction of an immune response against the most prevalent immunotypes, L1, L2, and L3,7,9, synthetic as well as native LPS-derived oligosaccharides were conjugated with tetanus toxoid. L3,7,9 phosphoethanolamine (PEA) group-containing oligosaccharide-tetanus toxoid conjugates evoked high immunoglobulin G (IgG) antibody levels in rabbits which were detected by an L2-, L3,7,9-, and, depending on the antiserum, L1-specific enzyme-linked immunosorbent assay (ELISA). Inhibition studies revealed that an identical antibody population was detected by L1 and L3,7,9 ELISA, indicating a similar tertiary structure of the inner core oligosaccharide of these two immunotypes. These antibodies recognize PEA group-containing epitopes present on the L1 and L3,7,9 LPS. An L2 PEA group-containing oligosaccharide-tetanus toxoid conjugate elicited L2- and L3,7,9-specific IgG antibodies, but in contrast with the L3,7,9 conjugates, no L1-specific IgG antibodies were evoked. These results indicate that L1 and L2 LPS do not contain cross-reactive epitopes, whereas both L2 and L3,7,9 LPS and L1 and L3,7,9 LPS possess common determinants. Three linear oligosaccharides and one branched oligosaccharide, representing partial structures of the inner core oligosacchardes of meningococcal LPS, were synthesized. Only the branched synthetic oligosaccharide-containing conjugate was able to induce and L1- and L3,7,9-specific immune response, whereas the linear oligosaccharide-protein conjugates evoked L2-specific immune responses. The branched oligosaccharide (beta-D-Glcp(1----4)-[L-alpha-D-Hepp(1----3)]-L-alpha-D-Hepp ) is therefore considered a minimal structure required for the induction of an immune response against L1 and L3,7,9 LPS and part of a cross-reactive epitope between these two immunotypes. For L2-specific immune responses, oligosaccharide structures terminating in beta-D-Glcp(1----4), alpha-D-GlcNAcp(1----2), or L-alpha-D-Hepp(1----5) are needed. The results suggest that it is possible to prepare an oligosaccharide structure with the ability to evoke an immune response against L1, L2, and L3,7,9 LPS. A feasible structure for such a "hybrid" oligosaccharide is discussed.
Related Articles
Functional Characterization of Lpt3 and Lpt6, the Inner-Core Lipooligosaccharide Phosphoethanolamine Transferases from Neisseria meningitidis▿
Wenzel, Cory Q.
St. Michael, Frank
Stupak, Jacek
Li, Jianjun
Cox, Andrew D.
Richards, James C.
Journal of Bacteriology
The lipooligosaccharide (LOS) of Neisseria meningitidis contains heptose (Hep) residues that are modified with phosphoethanolamine (PEtn) at the 3 (3-PEtn) and/or 6 (6-PEtn) position. The lpt3 (NMB2010) and lpt6 (NMA0408) genes of N. meningitidis, which are proposed to encode the required HepII 3- and 6-PEtn transferases, respectively, were cloned and overexpressed as C-terminally polyhistidine-tagged fusion proteins in Escherichia coli and found to localize to the inner membrane, based on sucrose density gradient centrifugation. Lpt3-His6 and Lpt6-His6 were purified from Triton X-100-solubilized membranes by nickel chelation chromatography, and dot blot analysis of enzymatic reactions with 3-PEtn- and 6-PEtn-specific monoclonal antibodies demonstrated conclusively that Lpt3 and Lpt6 are phosphatidylethanolamine-dependent LOS HepII 3- and 6-PEtn transferases, respectively, and that both enzymes are capable of transferring PEtn to both fully acylated LOS and de-O-acylated (de-O-Ac) LOS. Further enzymatic studies using capillary electrophoresis-mass spectrometry (MS) demonstrated that both Lpt3 and Lpt6 are capable of transferring PEtn to de-O-Ac LOS molecules already containing PEtn at the 6 and 3 positions of HepII, respectively, demonstrating that there is no obligate order of PEtn addition in the generation of 3,6-di-PEtn LOS moieties in vitro.
Related Articles
The (α2→8)-Linked Polysialic Acid Capsule and Lipooligosaccharide Structure Both Contribute to the Ability of Serogroup B Neisseria meningitidis To Resist the Bactericidal Activity of Normal Human Serum
Kahler, C. M.
Martin, L. E.
Shih, G. C.
Rahman, M. M.
Carlson, R. W.
Stephens, D. S.
Infection and Immunity
The molecular basis for the resistance of serogroup B Neisseria meningitidis to the bactericidal activity of normal human sera (NHS) was examined with a NHS-resistant, invasive serogroup B meningococcal isolate and genetically and structurally defined capsule-, lipooligosaccharide (LOS)-, and sialylation-altered mutants of the wild-type strain. Expression of the (α2→8)-linked polysialic acid serogroup B capsule was essential for meningococcal resistance to NHS. The very NHS-sensitive phenotype of acapsular mutants (99.9 to 100% killed in 10, 25, and 50% NHS) was not rescued by complete LOS sialylation or changes in LOS structure. However, expression of the capsule was necessary but not sufficient for a fully NHS-resistant phenotype. In an encapsulated background, loss of LOS sialylation by interrupting the α2,3 sialyltransferase gene, lst, increased sensitivity to 50% NHS. In contrast, replacement of the lacto-N-neotetraose α-chain (Galβ1-4GlcNAcβ1-3Galβ1-4Glc) with glucose extensions (GlcN) in a galE mutant resulted in a strain resistant to killing by 50% NHS at all time points. Encapsulated meningococci expressing a Hep2(GlcNAc)→KDO2→lipid A LOS without an α-chain demonstrated enhanced sensitivity to 50% NHS (98% killed at 30 min) mediated through the antibody-dependent classical complement pathway. Encapsulated LOS mutants expressing truncated Hep2→KDO2→lipid A and KDO2→lipid A structures were also sensitive to 50% NHS (98 to 100% killed at 30 min) but, unlike the wild-type strain and mutants with larger oligosaccharide structures, they were killed by hypogammaglobulinemic sera. These data indicate that encapsulation is essential but that the LOS structure contributes to the ability of serogroup B N. meningitidis to resist the bactericidal activity of NHS.
Related Articles
Improvement of Immunogenicity of Meningococcal Lipooligosaccharide by Coformulation with Lipidated Transferrin-Binding Protein B in Liposomes: Implications for Vaccine Development
Mistretta, Noëlle
Guy, Bruno
Bérard, Yves
Dalençon, François
Fratantonio, Olivia
Grégoire, Christophe
Lechevallier, Aurélie
Lhéritier, Philippe
Revet, Laurent
Moreau, Monique
Haensler, Jean
Rokbi, Bachra
Clinical and Vaccine Immunology : CVI
Among various meningococcal antigens, lipooligosaccharide (LOS) and recombinant lipidated transferrin-binding protein B (rlip-TbpB) are considered to be putative vaccine candidates against group B Neisseria meningitidis. In the present work, we report the development of a new liposome-based vaccine formulation containing both rlip-TbpB and L8 LOS. The endotoxic activity of the liposomal LOS was evaluated in vitro using the Limulus Amebocyte Lysate assay and compared to the endotoxic activity of free LOS. Above a 250:1 lipid/LOS molar ratio, liposomes were shown to effectively detoxify the LOS as the endotoxic activity of the LOS was reduced by more than 99%. Immunogenicity studies in rabbits showed that the presence of rlip-TbpB dramatically increased the immunogenicity of the LOS. While the formulation raised a strong anti-TbpB response, it elicited a higher anti-LOS IgG level than the liposomal LOS alone. Sera from rabbits immunized with rlip-TbpB/liposomal LOS displayed increased ability to recognize LOS on live bacteria expressing the L8 immunotype and increased anti-LOS-specific bactericidal activity compared to sera from rabbits immunized with liposomal LOS alone. Measurement of interleukin-8 (IL-8) produced by HEK293 cells transfected with Toll-like receptor (TLR) after stimulation with rlip-TbpB showed that the protein is a TLR2 agonist, which is in accordance with the structure of its lipid. Furthermore, an in vivo study demonstrated that the lipid moiety is not only required for its adjuvant effect but also has to be linked to the protein. Overall, the rlip-TbpB/LOS liposomal formulation was demonstrated to induce an effective anti-LOS response due to the adjuvant effect of rlip-TbpB on LOS.
Related Articles
Complete Genome Sequence of Neisseria meningitidis Serogroup A Strain NMA510612, Isolated from a Patient with Bacterial Meningitis in China
Zhang, Yan
Yang, Jian
Xu, Li
Zhu, Yafang
Liu, Bo
Shao, Zhujun
Zhang, Xiaobing
Jin, Qi
Genome Announcements
Serogroup A meningococcal strains have been involved in several pandemics and a series of epidemics worldwide in the past. Determination of the genome sequence of the prevalent genotype strain will help us understand the genetic background of the evolutionary and epidemiological properties of these bacteria. We sequenced the complete genome of Neisseria meningitidis NMA510612, a clinical isolate from a patient with meningococcal meningitis.
Related Articles
Enhanced Factor H Binding to Sialylated Gonococci Is Restricted to the Sialylated Lacto-N-Neotetraose Lipooligosaccharide Species: Implications for Serum Resistance and Evidence for a Bifunctional Lipooligosaccharide Sialyltransferase in Gonococci
Gulati, Sunita
Cox, Andrew
Lewis, Lisa A.
Michael, Frank St.
Li, Jianjun
Boden, Ryan
Ram, Sanjay
Rice, Peter A.
Infection and Immunity
We isolated serologically identical (by serovar determination and porin variable region [VR] typing) strains of Neisseria gonorrhoeae from an infected male and two of his monogamous female sex partners. One strain (termed 398078) expressed the L1 (Galα1 → 3Galβ1 → 4Glcβ1 → 4HepI) lipooligosaccharide (LOS) structure exclusively; the other (termed 398079) expressed the lacto-N-neotetraose (LNT; Galβ1 → 4GlcNAcβ1 → 3Galβ1 → 4Glcβ1 → 4HepI) LOS structure. The strain from the male index case expressed both glycoforms and exhibited both immunotypes. Nuclear magnetic resonance analysis revealed that sialic acid linked to the terminal Gal of L1 LOS via an α2 → 6 linkage and, as expected, to the terminal Gal of LNT LOS via an α2→ 3 linkage. Insertional inactivation of the sialyltransferase gene (known to sialylate LNT LOS) abrogated both L1 LOS sialylation and LNT LOS sialylation, suggesting a bifunctional nature of this enzyme in gonococci. Akin to our previous observations, sialylation of the LNT LOS of strain 398079 enhanced the binding of the complement regulatory molecule, factor H. Rather surprisingly, factor H did not bind to sialylated strain 398078. LOS sialylation conferred the LNT LOS-bearing strain complete (100%) resistance to killing by even 50% nonimmune normal human serum (NHS), whereas sialylation of L1 LOS conferred resistance only to 10% NHS. The ability of gonococcal sialylated LNT to bind factor H confers high-level serum resistance, which is not seen with sialylated L1 LOS. Thus, serum resistance mediated by sialylation of gonococcal L1 and LNT LOS occurs by different mechanisms, and specificity of factor H binding to sialylated gonococci is restricted to the LNT LOS species.
Related Articles
Two glycosyltransferase genes, lgtF and rfaK, constitute the lipooligosaccharide ice (inner core extension) biosynthesis operon of Neisseria meningitidis.
Kahler, C M
Carlson, R W
Rahman, M M
Martin, L E
Stephens, D S
Journal of Bacteriology
We have characterized an operon required for inner-core biosynthesis of the lipooligosaccharide (LOS) of Neisseria meningitidis. Using Tn916 mutagenesis, we recently identified the alpha-1,2-N-acetylglucosamine (GlcNAc) transferase gene (rfaK), which when inactivated prevents the addition of GlcNAc and alpha chain to the meningococcal LOS inner core (C. M. Kahler, R. W. Carlson, M. M. Rahman, L. E. Martin, and D. S. Stephens, J. Bacteriol. 178:1265-1273, 1996). During the study of rfaK, a second open reading frame (lgtF) of 720 bp was found upstream of rfaK. An amino acid sequence homology search of the GenBank and EMBL databases revealed that the amino terminus of LgtF has significant homology with a family of beta-glycosyltransferases involved in the biosynthesis of polysaccharides and O antigen of lipopolysaccharides. The chromosomal copy of lgtF was mutagenized with a nonpolar antibiotic resistance cassette to minimize potential polar effects on rfaK. Tricine sodium dodecyl sulfate-polyacrylamide gel electrophoresis and composition analysis of the LOS from the nonpolar lgtF mutant showed that this strain produced a truncated LOS structure which contained a LOS inner core of GlcNAc1Hep2KDO2lipid A but without the addition of lacto-N-neotetraose to HepI or glucose to HepII. These results and the amino acid homology with beta-glycosyltransferases suggest that lgtF encodes the UDP-glucose:LOS-beta-1,4-glucosyltransferase which attaches the first glucose residue to HepI of LOS. Reverse transcriptase PCR and primer extension analysis indicate that both lgtF and rfaK are cotranscribed as a polycistronic message from a promoter upstream of lgtF. This arrangement suggests that completion of the LOS inner core and the initiation of the alpha chain addition are tightly coregulated in N. meningitidis.
Related Articles
Anti-Gal binds to pili of Neisseria meningitidis: the immunoglobulin A isotype blocks complement-mediated killing.
Hamadeh, R M
Estabrook, M M
Zhou, P
Jarvis, G A
Griffiss, J M
Infection and Immunity
alpha 1,3-Galactosyl antibodies (anti-Gal) are ubiquitous natural human serum and secretory polyclonal antibodies that bind to terminal galactose-alpha 1,3-galactose (alpha-galactosyl) residues. Serum immunoglobulin G (IgG) anti-Gal can block alternative complement pathway-mediated lysis of representative gram-negative enteric bacteria that bind it to lipopolysaccharide alpha-galactosyl structures, thereby promoting survival of such bacteria in the nonimmune host. We wanted to know whether anti-Gal also could bind to the lipooligosaccharides (LOS) of Neisseria meningitidis. To our surprise, we found that serum and secretory anti-Gal bound to pili but not to LOS of certain strains. This suggested the presence of an immunogenic pilus carbohydrate epitope. Mild periodate oxidation of sodium dodecyl sulfate-polyacrylamide gel electrophoresis-separated outer membrane preparations from strains that bound anti-Gal followed by labeling of the neoaldehyde groups resulted in the labeling of bands that corresponded to pilin and LOS, confirming that pilin contains carbohydrate structures. A Bandeiraea simplicifolia lectin that also binds terminal alpha 1,3-galactosyl residues also bound to pilin. Serum IgG, IgA, and IgM anti-Gal as well as colostral secretory IgA anti-Gal bound to pilin, as judged by immunoblotting, and to the pili of intact piliated organisms, as judged by immunoelectron microscopy. Total serum anti-Gal (IgG, IgA, and IgM) and purified serum IgA1 anti-Gal, but not its purified IgG isotype, blocked complement-mediated lysis of a piliated meningococcal strain that bound anti-Gal to its pili. Colostral anti-Gal secretory IgA blocked killing of the same strain. Thus, anti-Gal IgA may promote disease when it binds to the pili of N. meningitidis strains.
Related Articles
Lipooligosaccharides (LOS) of some Haemophilus species mimic human glycosphingolipids, and some LOS are sialylated.
Mandrell, R E
McLaughlin, R
Aba Kwaik, Y
Lesse, A
Yamasaki, R
Gibson, B
Spinola, S M
Apicella, M A
Infection and Immunity
The lipooligosaccharides (LOS) of strains of Haemophilus ducreyi, Neisseria gonorrhoeae, Neisseria meningitidis, and Neisseria lactamica contain epitopes that are antigenically and structurally similar to carbohydrates present in human glycosphingolipids. LOS from strains of Haemophilus influenzae and H. influenzae biogroup aegyptius were tested for the binding of monoclonal antibodies (MAbs) that bind to human glycosphingolipids possessing Gal beta 1-4GlcNAc (MAb 3F11) and Gal alpha 1-4Gal beta 1-4Glc (MAb anti-Pk). In solid-phase radioimmunoassays, the LOS of 18 of 19 H. influenzae type b (Hib), 8 of 19 nontypeable H. influenzae, and 10 of 20 H. influenzae biogroup aegyptius strains bound MAb anti-Pk. The LOS of 13 of 19 Hib, 10 of 16 nontypeable H. influenzae, and 2 of 18 H. influenzae biogroup aegyptius strains bound MAb 3F11. Neuraminidase treatment of the strains increased the binding of MAb 3F11 by more than twofold in 47% of the H. influenzae strains, suggesting that sialic acid occluded the LOS structure recognized by MAb 3F11. The material released from neuraminidase-treated Hib LOS was confirmed to be sialic acid by high-performance anion-exchange chromatography. A recombinant plasmid containing genes involved in Hib LOS biosynthesis directed the expression (assembly) of the 3F11 epitope in Escherichia coli. These studies demonstrate that H. influenzae and H. influenzae biogroup aegyptius express at least two LOS epitopes that are similar to those present in human glycosphingolipids. Sialic acid was present on the LOS of some H. influenzae strains and prevented the binding of MAb 3F11 to its epitope. The oligosaccharide portion of sialylated LOS may also resemble sialylated oligosaccharides present in human glycosphingolipids (gangliosides).
Related Articles
The Development of an Experimental Multiple Serogroups Vaccine for Neisseria meningitidis
Pinto, Valerian B.
Burden, Robert
Wagner, Allyn
Moran, Elizabeth E.
Lee, Che-Hung
PLoS ONE
A native outer membrane vesicles (NOMV) vaccine was developed from three antigenically diverse strains of Neisseria meningitidis that express the L1,8, L2, and L3,7 lipooligosaccharide (LOS) immunotypes, and whose synX, and lpxL1 genes were deleted.. Immunogenicity studies in mice showed that the vaccine induced bactericidal antibody against serogroups B, C, W, Y and X N. meningitidis strains. However, this experimental NOMV vaccine was not effective against serogroup A N. meningitidis strains. N. meningitidis capsular polysaccharide (PS) from serogroups A, C, W and Y were effective at inducing bactericidal antibody when conjugated to either tetanus toxoid or the fHbp1-fHbp2 fusion protein fHbp(1+2). The combination of the NOMV vaccine and the N. meningitidis serogroup A capsular polysaccharide (MAPS) protein conjugate was capable of inducing bactericidal antibodies against a limited number of N. meningitidis strains from serogroups A, B, C, W, Y and X tested in this study.
Related Articles
Heterogeneity and variation among Neisseria meningitidis lipopolysaccharides.
Tsai, C M
Boykins, R
Frasch, C E
Journal of Bacteriology
Eight immunotype lipopolysaccharides (LPSs) of Neisseria meningitidis were prepared by the phenol-water procedure and characterized by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and sugar analyses. By SDS-PAGE and a highly sensitive silver strain. N. meningitidis LPSs from cells grown in tryptic soy broth were shown to contain one or two predominant components and a few minor, somewhat higher-molecular-weight components. The molecular sizes of the two predominant components were approximately the same as those of two E. coli rough-type LPSs, one with a complete core and the other with an incomplete core. The molecular weight of the major LPS component varied somewhat among different immunotypes but was estimated to be in the range of 4,200 to 5,000. By sugar analyses, the eight immunotype LPSs were different in their monosaccharide compositions. All contained glucose, galactose, heptose, glucosamine, and 2-keto-3-deoxyoctonate, but in different molar ratios. The growth of N. meningitidis in tryptic soy broth under different levels of aeration resulted in a change in the two major LPS components seen on the SDS-PAGE gel. High aeration increased the amount of the smaller component, whereas low aeration increased the amount of the larger component. Sugar analyses of LPSs from high and low aeration indicated that the larger LPS component contained more galactose residues per molecule. Use of different media for cell growth may also result in small, but noticeable, variations in the LPS components and in the galactose content of the LPS. The observed heterogeneity of N. meningitidis LPS may explain why many strains of N. meningitidis appear to possess more than one immunotype.
Related Articles
Microheterogeneity of Neisseria lipooligosaccharide: analysis of a UDP-glucose 4-epimerase mutant of Neisseria meningitidis NMB.
Lee, F K
Stephens, D S
Gibson, B W
Engstrom, J J
Zhou, D
Apicella, M A
Infection and Immunity
Neisseria meningitidis is the etiologic agent of epidemic bacterial meningitis. Lipooligosaccharide (LOS) is a principal virulence factor associated with the organism, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of LOS has demonstrated that there is considerable microheterogeneity in the molecule. To begin our understanding of the nature of this heterogeneity, we identified a Tn916-generated LOS mutant of N. meningitidis NMB (serotype L3, monoclonal antibodies 3F11+, 6B4+, and 4C4-) that was designated NMB-SS3 (monoclonal antibodies 3F11-, 6B4-, and 4C4+). The transposon insertion was localized to the amino terminus of the functional copy of the UDP-Glc 4-epimerase gene (galE). UDP-Glc 4-epimerase (EC 184.108.40.206) activity was present in N. meningitidis NMB but not in NMB-SS3, indicating that the Tn916 insertion had abolished this activity. Mass spectrometric analysis of the LOS from strain NMB revealed multiple species of LOS, which is consistent with extensive microheterogeneity. While the most predominant structure was consistent with a terminal lacto-N-neotetrose structure found in other strains of N. meningitidis, Gal beta 1-->4GlcNAc beta 1-->3Gal beta 1-->4Glc-->(GlcNAc)-->Hep2PEA-->KDO2 (where Hep is heptose, PEA is phosphoethanolamine, and KDO is 2-keto-3-deoxymannooctulosonic acid), structures containing repetitive hexoses which are not precursors of this structure were also identified. Compositional analysis of LOS from strain NMB-SS3 revealed that there were no galactoses present in the structure. Mass spectrometric analysis of O-deacylated LOS revealed the presence of multiple species, with the predominant LOS species in this mutant strain formed by the Hex-->(HexNAc)-->Hep2PEA-->KDO2 (where Hex is hexose and HexNAc is N-acetylhexosamine) structure. However, LOS structures with repetitive hexoses, e.g., Hexn-->(HexNAc)-->Hep2PEA-->KDO2 (n = 2, 3, or 4), emanating from one or both heptoses were also identified. Since this mutant cannot synthesize UDP-Gal, these structures must repetitive glucoses. These data suggest that NMB has a glycosyltransferase capable of polymerizing glucose moieties as an alternative biosynthetic pathway to the wild-type lacto-N-neotetrose structure.
Related Articles
Meningococcal lipopolysaccharides: virulence factor and potential vaccine component.
Verheul, A F
Snippe, H
Poolman, J T
Microbiological Reviews
Lipopolysaccharides (LPS) are surface components of the outer membrane of Neisseria meningitidis. Today, 12 different types of meningococcal LPS (immunotypes) are known, of which 3 are prevalent in the western world. The differences between these immunotypes are in the oligosaccharide part of the LPS molecule and consist of small differences in the oligosaccharide structure, the amount and location of phosphoethanolamine groups, and the degree of O acetylation of individual monosaccharides. Although the differences between the various immunotypes are small, they have a profound influence on the immunochemical and immunological properties of these molecules. Furthermore, each individual strain synthesizes a number of different LPS molecules. The expression of the various components (protective epitopes) is influenced by growth conditions and growth phase. Meningococci can endogenously sialyate their LPS, which constitutes one of the mechanisms by which N. meningitidis can evade the response of the human host. Meningococcal LPS play a key role in the induction of septic shock and can probably enhance the invasiveness of meningococcal strains and shield protective epitopes. Therefore, incorporation of (detoxified) LPS or oligosaccharide components derived therefrom might be very beneficial for the efficacy of a vaccine against group B meningococci. An overview of the development of vaccines against group B meningococci is given, and the status and potential of meningococcal LPS-derived (synthetic) oligosaccharide-protein conjugate vaccines are discussed.
Related Articles
Lipooligosaccharide Structure Contributes to Multiple Steps in the Virulence of Neisseria meningitidis
Plant, Laura
Sundqvist, Johanna
Zughaier, Susu
Lövkvist, Lena
Stephens, David S.
Jonsson, Ann-Beth
Infection and Immunity
Lipooligosaccharide (LOS) of Neisseria meningitidis has been implicated in meningococcal interaction with host epithelial cells and is a major factor contributing to the human proinflammatory response to meningococci. LOS mutants of the encapsulated N. meningitidis serogroup B strain NMB were used to further determine the importance of the LOS structure in in vitro adherence and invasion of human pharyngeal epithelial cells by meningococci and to study pathogenicity in a mouse (CD46 transgenic) model of meningococcal disease. The wild-type strain [NeuNAc-Galβ-GlcNAc-Galβ-Glcβ-Hep2 (GlcNAc, Glcα) 3-deoxy-d-manno-2-octulosonic acid (KDO2)-lipid A; 1,4′ bisphosphorylated], although poorly adherent, rapidly invaded an epithelial cell layer in vitro, survived and multiplied early in blood, reached the cerebrospinal fluid, and caused lethal disease in the mouse model. In contrast, the Hep2 (GlcNAc) KDO2-lipid A (pgm) mutant, which was highly adherent to cultured epithelial cells, caused significantly less bacteremia and mortality in the mouse model. The Hep2-KDO2-lipid A (rfaK) mutant was shown to be moderately adherent and to cause levels of bacteremia and mortality similar to those caused by the wild-type strain in the mouse model. The KDO2-lipid A (gmhB) mutant, which lacks the heptose disaccharide in the inner core of LOS, avidly attached to epithelial cells but was otherwise avirulent. Disease development correlated with expression of specific LOS structures and was associated with lower adherence but rapid meningococcal passage to and survival in the bloodstream, induction of proinflammatory cytokines, and the crossing of the blood-brain barrier. Taken together, the results of this study further define the importance of the LOS structure as a virulence component involved in multiple steps in the pathogenesis of N. meningitidis.
Related Articles
Genome Analysis and Strain Comparison of Correia Repeats and Correia Repeat-Enclosed Elements in Pathogenic Neisseria
Liu, Shi V.
Saunders, Nigel J.
Jeffries, Alex
Rest, Richard F.
Journal of Bacteriology
Whole genome sequences of Neisseria meningitidis strains Z2491 and MC58 and Neisseria gonorrhoeae FA1090 were analyzed for Correia repeats (CR) and CR-enclosed elements (CREE). A total of 533, 516, and 256 copies of CR and 270, 261, and 102 copies of CREE were found in these three genomes, respectively. The lengths of CREE range from 28 to 348 bp, and the lengths of multicopy CREE appear mainly in the ranges of 154 to 156 bp and 105 to 107 bp. The distribution of CREE lengths is similar between the two N. meningitidis genomes, with a greater number of 154- to 156-bp CREE (163 and 152 copies in N. meningitidis strain Z2491 and N. meningitidis strain MC58, respectively) than 105- to 107-bp CREE (72 and 77 copies). In the N. gonorrhoeae strain FA1090 genome there are relatively more 105- to 107-bp CREE (51 copies) than 154- to 156-bp CREE (36 copies). The genomic distribution of 107-bp CREE also shows similarity between the two N. meningitidis strains (15 copies share the same loci) and differences between N. meningitidis strains and N. gonorrhoeae FA1090 (only one copy is located in the same locus). Detailed sequence analysis showed that both the terminal inverted repeats and the core regions of CREE are composed of distinct basic sequence blocks. Direct TA dinucleotide repeats exist at the termini of all CREE. A survey of DNA sequence upstream of the sialyltransferase gene, lst, in several Neisseria isolates showed that 5 N. meningitidis strains contain a 107-bp CREE in this region but 25 N. gonorrhoeae strains show an exact absence of a 105-bp sequence block (i.e., the 107-bp CREE without a 5′ TA dinucleotide) in the same region. Whole-genome sequence analysis confirmed that this 105-bp indel exists in many homologous 107-bp CREE loci. Thus, we postulate that all CREE are made of target TA with indels of various lengths. Analysis of 107-bp CREE revealed that they exist predominantly in intergenic regions and are often near virulence, metabolic, and transporter genes. The abundance of CREE in Neisseria genomes suggests that they may have played a role in genome organization, function, and evolution. Their differential distribution in different pathogenic Neisseria strains may contribute to the distinct behaviors of each Neisseria species.
Related Articles
Comparative Analysis of Two Meningococcal Immunotyping Monoclonal Antibodies by Resonant Mirror Biosensor and Antibody Gene Sequencing
Charalambous, Bambos M.
Evans, Janet
Feavers, Ian M.
Maiden, Martin C. J.
Clinical and Diagnostic Laboratory Immunology
Lipooligosaccharide (LOS) is a major surface component of the cell walls of Neisseria meningitidis, which is important for its roles in pathogenesis and antigenic variation, as a target for immunological typing, and as a possible vaccine component. Although the structures of many antigenic variants have been determined, routine immunological typing of these molecules remains problematic. Resonant mirror analysis was combined with gene sequencing to characterize two monoclonal antibodies (MAbs) used in typing panels that were raised against the same LOS immunotype, L3,7,9. The two MAbs (MAb 4A8-B2 and MAb 9-2-L379) were of the same immunoglobulin subtype, but while MAb 9-2-L379 was more than a 1,000-fold more sensitive in immunotyping assays of both whole meningococcal cells and purified LOS, MAb 4A8-B2 was more specific for immunotype L3,7,9. The differences in sensitivity were a consequence of MAb 9-2-L379 having a 44-fold-faster association constant than MAb 4A8-B2. Comparison of the amino acid sequences of the variable chains of the MAbs revealed that they had very similar heavy chains (81% amino acid sequence identity) but diverse light chains (54% sequence identity). The differential binding kinetics and specificities observed with these MAbs were probably due to differences in the epitopes recognized, and these were probably a consequence of the different immunization protocols used in their production.
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text:
BARACK OBAMA BIRTH CERTIFICATE: Suit contesting Obama's citizen...
There are 228038 comments on the Chicago Tribune story from Jan 8, 2009, titled BARACK OBAMA BIRTH CERTIFICATE: Suit contesting Obama's citizen.... In it, Chicago Tribune reports that:The U.S. Supreme Court will consider Friday whether to take up a lawsuit challenging President-elect Barack Obama 's U.S. citizenship, a continuation of a New Jersey case embraced by some opponents of Obama's ...
Join the discussion below, or Read more at Chicago Tribune.
#147204 Mar 15, 2013
... Special Report With Brett Baier... Three Benghazi Survivors Interviewed ?
taqiyyologist says:
March 16, 2013 at 1:13 am
SEALs are no joke. And weve lost how many since this farce of a Bringing Jeffersonian Democratic Culture To The Heart of Islam Without Simultaneously Bringing The Gospel Because That Would Be Bad And Without Also Giving Them The Hiroshima Treatment At Mecca Because That Would Be Bad Too joke of a war?
Its not a war, its a trap.
#147205 Mar 15, 2013
the latest...Congress is now involved in Obama's fraudulent docs...they met today...at CPAC. He is going to be impeached at the very least. It is just a matter of time.
#147207 Mar 15, 2013
Thank You!
Sulaymaniyah, Iraq
#147208 Mar 15, 2013
About 3 years and 10 months time.
#147209 Mar 16, 2013
^^^ It's a plagiarist!
#147210 Mar 16, 2013
Its called 'Delusion' when wishful thinking becomes confused with reality...something that is epidemic on the Right these days.
Since: Oct 09
#147211 Mar 16, 2013
Perhaps McCain and Romney should have run against Bush as well.
Think Bobby could have been President of anything save his district Frank?
#147212 Mar 16, 2013
You seem unable to come to grips with fact that you and those like you lost.
The entire slate of your paranoid Rightist fanaticism was REJECTED (for the second time).
Apparently the Repubs LOSING the popular vote by the Majority of Americans FIVE times in the last SIX elections hasnt sunk in as a possible indication of just how irrelevant and out of touch you dingbats truly are.
You guys arent to quick on the old uptake are you?
What a ridiculous conceit that you STILL act like your on the verge of some big 'comeback' Hah!
#147213 Mar 16, 2013
You shrill Psycotic cow.
You and LRS get mocked everywhere you go for a variety of reasons.
Your both completely on the wrong side of nearly every issue you repeat lies and distortions from the rightwing blogosphere as if they were gospel.
You subscribe to a conspiracy theory that has been debunked time and again yet you WANT it to be true so bad you cant let go of it.
Your both to the point of confusing your own wishful thinking with reality to the point of mental illness.
You come across as sanctimonius and self rightous to the point of parody and LRS seems to think being a smarmy sarcastic troll is a substitute for having ANYTHING of substance to back up his position.
He's kind of like a five year old who manages to get a laugh then keeps doing the same thing over and over for hours without being smart enough to realize its just old and hasnt been funny for a loooong time.
Quit flattering yourself you arent visionaries your just fools who deserve to be mocked.
Since: Oct 09
#147214 Mar 16, 2013
Why must you continue to make up stuff Frank?
What I am opposed to is a dumb war. What I am opposed to is a rash war. What I am opposed to is the cynical attempt by Richard Perle and Paul Wolfowitz and other armchair, weekend warriors in this administration to shove their own ideological agendas down our throats, irrespective of the costs in lives lost and in hardships borne.
What I am opposed to is the attempt by political hacks like Karl Rove to distract us from a rise in the uninsured, a rise in the poverty rate, a drop in the median income to distract us from corporate scandals and a stock market that has just gone through the worst month since the Great Depression. That's what I'm opposed to. A dumb war. A rash war. A war based not on reason but on passion, not on principle but on politics. Now let me be clear I suffer no illusions about Saddam Hussein. He is a brutal man. A ruthless man. A man who butchers his own people to secure his own power. He has repeatedly defied UN resolutions, thwarted UN inspection teams, developed chemical and biological weapons, and coveted nuclear capacity. He's a bad guy. The world, and the Iraqi people, would be better off without him.
But I also know that Saddam poses no imminent and direct threat to the United States or to his neighbors, that the Iraqi economy is in shambles, that the Iraqi military a fraction of its former strength, and that in concert with the international community he can be contained until, in the way of all petty dictators, he falls away into the dustbin of history
#147215 Mar 16, 2013
Wow your really reaching Bug-Boy Laity.
More Hitler analogies?
Your garbage is getting threadbare and weak.
You realise that all the people in your life who have suggested that you have a Mental Illness cant ALL be wrong?
Since: Oct 09
#147216 Mar 16, 2013
Poor Rogue!
Since: Oct 09
#147217 Mar 16, 2013
I have no problem with one reporting the facts as they are Cmor. However I do become concerned when a substantial portion of the populace cannot discern fact from fiction.
Since: Oct 09
#147218 Mar 16, 2013
You dont know how close you are to being right on that one Cmor. I bought the heater a month ago and its been in my van since because Ive been too lazy to install the damn thing. The old one still heats as well as always but it was leaking water from the bottom and couldnt be repaired. No cold showers just the irritation of dumping a few pans of water.
Since: Oct 09
#147219 Mar 16, 2013
No Ones ever debunked this one either Rogue.
#147220 Mar 16, 2013
I think its pretty clear where exactly Rogue extracts his political acumen from.
Thanks Poppo,as 'LRS' is so fond of saying ad nauseum;LMFAO!
So what do ya have to say for yourself there 'Rogue'?
What makes you think your 'insight' has improved one bit since you posted this stuff?
Toronto, Canada
#147221 Mar 16, 2013
Oh okay, then Portman is lying.
"On Deck"
Since: Aug 08
#147222 Mar 16, 2013
It is absurb to say that Saddam Hussein was not a real threat to his neighbors and, more importantly, the vital strategic interests of the United States.
Maybe you and Barack Obama were asleep when the Butcher of Bahgdad overran Kuwait and deliberately created one of the world's biggest environmental, ecological, and economic disasters ever known to mankind.
Were you asleep when Hussein adopted a scorched earth policy and torched over 700 of the world's most productive oil wells?
Or were you comatose?
Toronto, Canada
#147223 Mar 16, 2013
Dr PhD ha ha. PhD from Dennis Rodman University. Thank you, it's great to start the day with a good joke.
Toronto, Canada
#147224 Mar 16, 2013
Er, Truman, Rogue wrote to me the other day that he never made one wrong prediction. I then listed about 10. Strangely, he never came back. You won't see a reply to Poppo's Rogue's famous predictions either. Or if he does react, he'll say it's the media's fault, like the Jacksonville mayoralty race.
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Comment of the Day: The Immigration Debate, With Some All-Caps Action
We have some great commenters here on Hair Balls, and it's time we paid some damn attention to them.
So we'll be highlighting a Comment of the Day each morning or afternoon from the previous day's work. Maybe two comments, even.
This will all be determined by a highly rigorous scientific formula involving wit, clarity and whatever else we feel like at the moment.
We looked at who would be allowed to stay in the country under President Obama's new rules, a mini-DREAM Act -- and wondered what exactly was wrong with allowing people to stay here, people who had nothing to do with the decision to cross the border, people who were in school, or served in the Armed Forces, people with clean criminal records.
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One reader put us straight, and because she used all-caps for important phrases, she must be right.
Pamela wrote:
They are border hoppers. They hopped our U.S. border with their Illegal Alien border hopping parents. Once here, they sat in our U.S. schools stealing a U.S. K-12 education, off of the backs of the Real American citizens, with their taxes. When these Illegal Aliens turned 18, becoming FULL GROWN ADULT ILLEGAL ALIENS, they CHOSE to continue to break our laws. They had the choice to do the right thing, leave our country, go back to theirs and come back, LEGALLY. But, with ILLEGALS you cannot expect them to do anything Legal. Lawless immoral criminal behavior, is their culture.
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text:
My Helping Hands
Ziggy MarleyBuy this song
These are my hands My hands are used for many things I brush my teeth with my hands I hug with my hands I even paint with my hands But what I really love to do most of all with my hands is help I help my dad to make breakfast with my hands I help my mom to unpack her bags when she comes from the store with my hands I help to change my baby brother with my hands I help to put my toys away with my hands I love to do many things with my hands but most of all i love to help with my hands My Helping Hands
Written by: DAVID NESTA MARLEY
Lyrics © EMI Music Publishing, Peermusic Publishing, Sony/ATV Music Publishing LLC, ISHTI MUSIC INC
Lyrics Licensed & Provided by LyricFind
Discuss the My Helping Hands Lyrics with the community:
Use the citation below to add these lyrics to your bibliography:
"My Helping Hands Lyrics." Lyrics.com. STANDS4 LLC, 2016. Web. 27 Oct. 2016. <http://www.lyrics.com/lyric/16832143>.


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I was talking about Rundra, I considered the Berserker Lord some kind of a sub boss. Anyway, the golem boss (dont remember the name), was even harder. I think I just suck with the motion controllers, but I'm not enjoying this. Which is a shame because I love the previous games (Prime 1 is in my opinion the best game ever made).
You are not allowed to request a sticky.


text:
Naperville Park District Golf Courses
The Naperville Park District Golf Operations is one of five operating departments within the Naperville Park District, and currently the District operates two 18-hole municipal golf facilities. Each facility offers a different golfing opportunity for players of all ages and abilities. One of the goals within the golf department is to provide challenging yet accessible and enjoyable golfing experiences to the residents of Naperville as well as to our nonresident guests at an affordable price.
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text:
From the Institute for Healthcare Delivery Science, Department of Population Health Science & Policy (Drs Özbek, Poeran, and Mazumdar), Tisch Cancer Institute (Drs Özbek and Mazumdar), and Department of Medicine (Dr Poeran), Icahn School of Medicine at Mount Sinai, New York, NY; Department of Healthcare Policy and Research (Dr Memtsoudis), Weill Cornell Medical College, and Department of Anesthesiology (Dr Memtsoudis), Hospital for Special Surgery, New York, NY; and Department of Anesthesiology, Perioperative Medicine and Intensive Care Medicine (Dr Memtsoudis), Paracelsus Medical University, Salzburg, Austria.
CORRESPONDENCE TO: Stavros G. Memtsoudis, MD, PhD, FCCP, Department of Anesthesiology, Hospital for Special Surgery, 535 E 70th St, New York, NY 10021; e-mail: firstname.lastname@example.com
FUNDING/SUPPORT: Drs Özbek and Mazumdar were partially supported by Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.
Despite literature suggesting benefits of using regional anesthesia, the impact of neuraxial anesthesia on perioperative outcomes in patients undergoing lung surgery remains unstudied. We studied the effect of combined neuraxial/general anesthesia (vs general anesthesia) on perioperative outcome in a large national sample of patients who underwent open lung resection.
We extracted data from the Premier Perspective database on patients who underwent open lung resection. The main effect of interest was anesthesia type: general and combined neuraxial/general anesthesia. Patient and health-care variables, complications, and resource use were compared between groups. Multivariable analyses assessed the independent impact of choice of anesthetic technique on outcomes.
For 18,943 patients, anesthesia type was known: 79% (n = 14,912) were administered general anesthesia, and 21% (n = 4,031) received neuraxial/general anesthesia. Comparing general vs neuraxial/general anesthesia, unadjusted incidences for the latter were lower for acute myocardial infarction (1.09% vs 0.67%, P = .018), pulmonary complications (20.96% vs 18.98%, P = .006), blood transfusion (14.15% vs 9.80%, P < .0001), and mechanical ventilation (11.60% vs 8.81%, P < .0001). Neuraxial/general anesthesia was associated with lower adjusted odds of blood transfusion (OR, 0.82; 95% CI, 0.69-0.98) and mechanical ventilation (OR, 0.81; 95% CI , 0.67-0.98), while higher odds were seen for DVT (OR, 1.50; 95% CI, 1.01-2.23) and pulmonary embolism (OR, 1.56; 95% CI, 1.02-2.38).
This study illustrates the association between adding neuraxial to general anesthesia in open lung resections among patients with cancer and perioperative outcomes. Neuraxial anesthesia use was associated with decreased risk for blood transfusion but increased thromboembolic risks. Additional studies are needed to elucidate mechanisms by which neuraxial anesthesia may affect these outcomes.
Approximately 400,000 Americans suffer from lung cancer, the leading cause of cancer death in the United States.1,2 To date, surgical resection represents the main curative approach and is performed approximately 40,000 times per year in the United States alone.3‐5 Despite improvements in surgical techniques and medical management, morbidity and mortality remain relatively high.6 In this context, many practitioners consider the use of neuraxial anesthetic techniques in an attempt to reduce complication rates.7,8
Current evidence is derived from small, single-institution studies suggesting better clinical outcomes with the use of neuraxial anesthesia (combined with general anesthesia), including less intraoperative bleeding, better control of postoperative pain, early mobilization, and oral intake tolerance.7,9‐13 However, large-scale data on anesthesia practices and outcomes, in particular for the United States, are lacking.
Such data are important, given that much of the estimated $12.1 billion per year spent on lung cancer treatment in the United States14 is related to the high use of resources (ie, critical care services, mechanical ventilation, prolonged hospital stay) and potentially high rates of perioperative complications.
In view of the available evidence suggesting benefits of neuraxial anesthesia in this and other patient populations,15 we aimed to (1) determine the extent of the use of neuraxial anesthesia among patients undergoing open resection surgery for lung cancer, and (2) quantify the impact of anesthetic technique on patient perioperative outcomes and resource utilization. We used data from a large, claims-based national database and hypothesized that the addition of neuraxial anesthesia to general anesthesia would positively affect various perioperative outcomes.
Data collected between 2006 and 2013 were obtained from Premier Perspective Inc, which is an administrative database containing information on all discharges from approximately 20% to 25% of hospitals located in the United States.16 This project was exempt from requirements for consent by our institutional review board (project HS No. 14-00647), as the data are compliant with the Health Insurance Portability and Accountability Act.
All patient records with an International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) procedure code for open lung resection performed between 2006 and 2013 were identified using codes for segmentectomy (32.39), lobectomy (32.49), and pneumonectomy (32.59). To keep the sample as homogenous as possible, we chose to study only open lung resections. This sample was further restricted to entries with ICD-9-CM codes for malignant neoplasm of main bronchus (162.2), malignant neoplasm of upper lobe bronchus or lung (162.3), malignant neoplasm of middle lobe bronchus or lung (162.4), malignant neoplasm of lower lobe bronchus or lung (162.5), malignant neoplasm of other parts of bronchus or lung (162.8), and malignant neoplasm of bronchus and lung unspecified (162.9). Elective, urgent, and emergent admissions were included. Using billing data as previously described,17 we separated entries into groups of patients, who underwent their procedure under general or combined neuraxial/general anesthesia. Those without indication of type of anesthesia were categorized as missing. To ensure that this step would not skew results, a sensitivity analysis was performed by including and by excluding patients with missing entry for all analyses.
We compared the characteristics of patients with lung cancer undergoing lung resection under the different types of anesthesia (general and neuraxial/general). Patient-related characteristics included age, sex, race (white, black, Hispanic, other), admission type (emergent, elective, urgent, and others), and insurance type (commercial, Medicaid, Medicare, uninsured). Health care-related characteristics included hospital size (< 299, 300-499, > 500 beds), geographic location (rural, urban), and teaching status (teaching, nonteaching). Comorbidity prevalence and overall comorbidity burden was assessed using the method described by Deyo et al.18 In addition, the extent of surgery (pneumonectomy, lobectomy, or segmentectomy) was taken into account.
Outcome variables were almost all identified by ICD-9-CM codes (e-Table 1) and incidence (or median) was shown by anesthesia group. Complications included acute renal failure, DVT, GI complications, cardiac complications (including conduction disorders, functional disturbances, ventricular fibrillation and flutter, atrial fibrillation and flutter, cardiac arrest, cardiac insufficiency, cardiorespiratory failure, and heart failure resulting from the procedure), acute myocardial infarction, cerebrovascular events, pulmonary complications overall, pulmonary embolism, pneumonia, mortality, and wound complications. Need for blood transfusion, admission to an ICU, need for mechanical ventilation, length of hospital stay, and cost of hospitalization were classified as resource utilization variables.
Patient demographics, health care- and procedure-related variables, and comorbidities were assessed and compared by anesthesia type. Categorical variables were compared using χ2 tests. Due to their skewed distribution, the difference between groups in continuous variables was tested using the Mann-Whitney U test. We used multilevel logistic regression modeling to assess the association between anesthesia types on outcomes. Correlation of patients within each hospital was accounted for by including a random intercept in the models. To meet the minimum recommended sample size cluster, only hospitals having ≥ 30 patients were included.19 Models were adjusted using all variables that were clinically important and found significant in the univariable analysis (P ≤ .15). The Deyo-Charlson Comorbidity Index was used to adjust for comorbidity status. ORs, 95% CIs, and P values are reported and are to be used together as a measure of overall significance. All analyses were performed in SAS version 9.3 statistical software (SAS Institute Inc); the GLIMMIX procedure was used for multilevel regression analyses.
We identified 21,756 patients with lung cancer who underwent open lung resections at 353 hospitals between 2006 and 2013. Among those, 90% (n = 19,611) were elective admissions, 6% (n = 1,294) were urgent, and 4% (n = 851) were emergent admissions. For 87% (n = 18,943) of those admissions, an entry for the type of anesthesia was available: 79% (n = 14,912) were performed under general anesthesia, and 21% (n = 4,031) were performed under combined neuraxial/general anesthesia. Table 1 shows the patient and health care-related variables by anesthesia type. There were no significant differences in age, sex, or insurance type. Most notably, patient race (P ≤ .0001) and hospital characteristics (size [P ≤ .0001], location [P ≤ .0001], and teaching status [P = .008]) were significantly associated with anesthesia type, with Medicare covering > 50% of patients across both anesthesia types and the majority of operations performed at urban hospitals. Furthermore, overall comorbidity burden did not differ between groups (P = .076) (Table 2).
P value is to test the null hypothesis of no incidence difference between general and neuraxial/general (χ2 test).
P value is to test the null hypothesis of no prevalence difference between general and neuraxial/general (χ2 test for categorical variables, Mann-Whitney U test for continuous variables).
Continuous variable median and lower and upper quartiles instead of No. and %, respectively.
Table 3 depicts outcomes by anesthesia type. Most notably, when comparing general vs neuraxial/general anesthesia, the latter appeared more favorable for incidences of acute myocardial infarction (1.09% vs 0.67%, P = .018), pulmonary complications (20.96% vs 18.98%, P = .006), blood transfusion (14.15% vs 9.80%, P < .0001), and mechanical ventilation (11.60% vs 8.81%, P < .0001). On the other hand, using the same comparison, we observed significantly higher incidence rates of DVT (0.83% vs 1.17%, P = .041), and pulmonary embolism (0.67% vs 0.99%, P = .034) in the neuraxial/general anesthesia group. There were no statistically significant differences in length of stay or cost of hospitalization between anesthesia groups.
P value is to test the null hypothesis of no incidence difference between general and neuraxial/general (χ2 test for categorical variables, Mann-Whitney U test for continuous variables).
Conduction disorders, functional disturbances, ventricular fibrillation and flutter, atrial fibrillation and flutter, cardiac arrest, cardiac insufficiency, cardiorespiratory failure, and heart failure resulting from procedure.
Data given as continuous variable median and lower and upper quartiles.
When we controlled for the covariates age, sex, race, geographic location, size of the hospital, comorbidity burden, extent of surgery, and admission type, with hospitals as random intercept in the models, combined neuraxial/general anesthesia (compared with general anesthesia) was associated with lower odds for blood product transfusion (OR, 0.82; 95% CI, 0.69-0.98; P = .027) and mechanical ventilation (OR, 0.81; 95% CI, 0.67-0.98; P = .029), while higher odds were observed for DVT (OR, 1.50; 95% CI, 1.01-2.23; P = .043), cerebrovascular events (OR, 1.59; 95% CI, 1.04-2.44; P = .035), and pulmonary embolism (OR, 1.56; 95% CI, 1.02-2.38; P = .043) (Table 4). There were no statistically significant associations with the anesthesia type for the other outcomes.
This table displays the results of the multivariable regression analysis for various complications and outcomes comparing combined neuraxial/general vs general (reference) anesthesia for patients receiving lung resection. For each outcome, logistic regression was used to evaluate its association with the type of anesthesia while controlling for age, sex, race (white, black, Hispanic, other), geographic location (urban or rural), hospital size, comorbidity burden, extent of surgery (pneumonectomy, lobectomy, or segmentectomy), admission type (elective, urgent, or emergent), and pulmonary complications.
Other pulmonary complications were not controlled for.
In this study of 21,756 hospitalized patients with lung cancer who underwent open lung resection surgery, we found that neuraxial anesthesia was used in approximately one-fifth of patients. The use of neuraxial techniques was associated with reduced risk for blood transfusions and mechanical ventilation, while odds were increased for thromboembolic and cerebrovascular events. The use of neuraxial in addition to general anesthesia failed to show an impact on other outcomes, including mortality and other resources.
Large randomized trials addressing optimal anesthesia in perioperative practice have not seemed feasible, given the costs and the number of patients needed to study the relatively low incidence of outcomes. Although some propose combined neuraxial and general anesthesia to be preferred over just general anesthesia in lung resections, these claims are based on results from relatively small and single-institution trials involving non-US patients.7,9‐13 Moreover, data are lacking on perioperative outcomes (eg, complication rates or mortality). Thus, available data on the proposed benefits of neuraxial anesthesia are burdened with significant limitations associated with small sample sizes and general applicability of results representing current practice.20‐24 Moreover, data are specially limited for patients undergoing noncardiac thoracic surgery, such as lung resections. There is another significant knowledge gap with respect to perioperative outcomes for subpopulations, which is becoming increasingly important in this age of patient-tailored medicine.
The availability of large national databases and advances in methodologic approaches provide opportunities to study perioperative outcomes in the context of different anesthesia practices in the US population. Similar to the current study, we used data from the large national Premier Perspective claims-based database for other published studies.16,25,26 In these studies, we compared perioperative outcome after general, neuraxial, and general/neuraxial anesthesia in (1) all patients undergoing primary joint (hip or knee) arthroplasty and (2) the subgroup of patients suffering from sleep apnea.25,26 These studies showed neuraxial and neuraxial/general anesthesia combined to be preferred over general anesthesia (in terms of patient safety outcomes and resource use) in all arthroplasty patients as well as in the subgroup of patients with sleep apnea, thus providing the first large-scale support, to our knowledge, for the widely used guidelines published by the American Society of Anesthesiologists in 2006 on the perioperative care of patients with sleep apnea.25,27
In this study, using a large nationwide sample, we were able to compare the effect of anesthesia types on perioperative outcomes after open lung resection among patients with cancer. While we were able to identify benefits for the outcomes of reduced need for blood transfusions and mechanical ventilation, patients receiving a neuraxial anesthetic had higher risk for thromboembolic events, including DVT, pulmonary embolism, and cerebrovascular accidents. The reasons for these findings have to remain speculative from our data, but possible explanations exist.
The addition of neuraxial to general anesthesia has been associated with a blunting of the sympathetic system, and, thus, leads to better BP control with subsequent less blood loss and transfusion, as observed in our study.13 A trend toward reduced myocardial ischemic events may equally be explained by such a mechanism. On the other hand, using neuraxial anesthesia may promote hypotension, which may be associated with cerebrovascular ischemic events. The increased risk of thromboembolic events may be linked to the inability to use more potent anticoagulants, especially if epidural catheters remain in place postoperatively, thus putting patients (especially those with cancer), known to be hypercoagulable, at increased risk for thrombotic complications.28 This mechanism might be responsible for the observed thromboembolic risk in our study. To test this hypothesis, we analyzed the use of anticoagulant medications in both groups of interest (e-Table 2) and were able to confirm this assumption: Anticoagulant use was significantly lower for all categories for patients undergoing their procedure under neuraxial/general anesthesia compared with those undergoing their procedure under general anesthesia.
Controversy has persisted among clinicians over the potential impact of the type of anesthesia on perioperative outcomes.20‐24 General anesthesia provides fast and effective anesthesia, muscle relaxation, and unawareness, but, unfortunately, contributes to unfavorable postoperative symptoms, such as nausea and vomiting, fatigue, and drowsiness.29,30 To provide effective postoperative analgesia, general anesthesia is often combined with neuraxial anesthesia.31
Compared with general anesthesia, neuraxial anesthesia has been associated with beneficial effects on intestinal perfusion, accelerated postoperative recovery of intestinal function, antiischemic effects due to postoperative stress reduction, and reduction of systemic sympathetic activity.9,13,32,33 An increasingly mentioned potential benefit of neuraxial anesthesia is the opioid-sparing effect and reduced neurohumoral stress response; in case of cancer surgery, some studies show reduced tumor recurrence and improved survival in procedures under neuraxial anesthesia.31,34 Possible side effects associated with neuraxial anesthesia comprise intraoperative hypotension, pruritus, urinary retention, respiratory depression, postdural puncture headache, and, most importantly, the risk of permanent neurologic damage, which is rare (0-4 per 10,000 applied spinal anesthetics).35
Our study has several limitations due to the analysis of secondary data from a large administrative database not originally intended for clinical research. First, detailed clinical information may not be available and the impact of that information cannot be assessed on outcome. Second, the database is based on discharges; therefore, it is not possible to detect the effect of repeated measures, such as people registered more than once. Moreover, it is not possible to capture postdischarge outcomes such as the incidence of postthoracotomy pain syndrome, a frequent and debilitating condition. In this context, a Cochrane review showed that the addition of neuraxial anesthesia was associated with improved outcomes at 6 months after surgery.36 Another limitation of our study pertains to the potential for coding bias because of the ICD-9-CM coding system for defining comorbidities, complications, and surgical pathology. However, both groups should have been exposed equally to such bias, thus diminishing its influence on comparative results. The true incidence of complications may not be captured and, indeed, may be underestimated due to the specific ICD-9-CM codes used (e-Table 1). Finally, we found 13% missingness of our effect variable of interest (ie, anesthesia type), using billing data for identification. This proportion of missingness compares well with that reported in the comprehensive National Anesthesia Clinical Outcomes Registry, which has a missing rate of around 18%37 and was designed specifically to capture anesthesia-related information. To investigate how this missingness would affect outcomes, however, we performed a sensitivity analysis and found no differences when including the missing subjects in our analyses.
In conclusion, using a large national sample, we demonstrate that choice of combined neuraxial/general anesthesia over general anesthesia alone has superior effect on the risk of blood transfusion and mechanical ventilation. However, adding neuraxial anesthesia was associated with increased risk of pulmonary embolism and DVT, which may be due to the reduced use of anticoagulant medications for fear of neuraxial hematoma formation. Combined neuraxial/general anesthesia may have benefits over general anesthesia only, but more effective anticoagulation strategies compatible with neuraxial techniques need to be established to avoid thromboembolic events. Based on these findings, further research should be conducted into mechanisms by which neuraxial anesthesia may affect these outcomes.
Author contributions: U. Ö. and J. P. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. U. Ö. served as principal author. U. Ö., J. P., and M. M. designed the study; M. M. and S. G. M. attained the Premier Perspective database; U. Ö. and J. P. analyzed data under guidance of M. M. and S. G. M.; and U. Ö., J. P., M. M., and S. G. M. contributed to the interpretation of the results and reviewed and approved the final manuscript.
Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
Other contributions: Data were purchased from Premier Inc and, as such, are restricted for this project and cannot be shared because of these restrictions on use of data. Syntax is available from the corresponding author. The authors thank Rehana Rasul, MA, MPH, for database management and creating the analytic datasets.
Additional information: The e-Tables can be found in the Supplemental Materials section of the online article.
International Classification of Diseases, Ninth Revision, Clinical Modification
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The Blind Owl
by Sadegh Hedayat, D.P. Costello, Porochista Khakpour
- #11724 in Fiction & Literature, Literary
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The young woman who haunts the narrator is first introduced as a stranger with jet-black hair and wide, haunting eyes. She creeps into the narrator's room but he realizes, upon touching her, that she is lifeless and cold. The narrator, a painter and opium addict, packs the woman's corpse into a suitcase and takes her to an remote spot along the banks of a river, where he buries her. Along the way he meets an old man with a spine-chilling laugh who becomes the first in a stream of recurring mental images: four cadaverous black horses with rasping coughs, a hidden urn of poisoned wine, a sheep butcher, and a small painting of a woman on the back of a pen-case soon follow. Through a series of intricately woven events that revolve around these images, the narrator is compelled to record his obsession with the woman even as it drives him further into madness. That the narrator is recording his confession for the sake of his shadow, which he thinks perfectly resembles an owl, only heightens the sense of terror: "My shadow on the wall had become exactly like an owl and, leaning forward, read intently every word I wrote."
The eerie images, and their repetition, obscure reality and twist and turn into themselves, disorienting the reader and mimicing the distress of the opium-addled narrator. The woman, at first a stranger, becomes the narrator's mother, and finally his wife. As the book winds to a close, the narrator is trapped in his room, so dissociated from reality that his shadow appears more real to him than he himself does. The narrator finally takes up his bone-handled butcher's knife (the same instrument he has seen the butcher wiping on the legs of sheep carcasses), and proceeds to the beautiful young woman's room. After she welcomes him in, he falls into -- or springs upon -- her, consumed by lust and hatred ("[they] were twins. Her fresh, moonlight-pale body . . . opened and closed me within itself like a cobra coiling around its prey"). In the confused, impassioned struggle that follows, the man sinks his knife into the young woman's side, killing her. Emitting a hollow, grating laugh, he staggers to a mirror -- only to find that his reflection is that of the old bearded man who has so long been haunting him. The book ends with the man looking out of his room to see the crouching figure of the old man disappearing into the mist, and looking down at his own chest to see maggots writing in the folds of his coat, and to feel the weight of the dead woman upon his chest.
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by on October 23, 2016
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- Grove/Atlantic, Inc., October 2010
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- 9780802196422
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Shake It Up 2010 | TV Show Watchlist
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Authorities investigating suspected suicide
MARIETTA – The Washington County Sheriff's Office is investigating a suspected self-inflicted fatal shooting at the Interstate 77 rest area north of Marietta.
Earl Johnson of Beverly was found dead around midnight Tuesday in a bathroom stall, according to Washington County Sheriff Larry Mincks.
There was a note with him, he said.
Mincks said a 911 call came in from the caretaker of the site, who said he had noticed the man go into the building but never come out and went to check on him.
"With the assistance of the Highway Patrol we conducted an investigation and found out the guy had left home and his wife indicated he was a little despondent," Mincks said. "We found him with a self-inflicted gunshot would to the head."
Though there was nothing to indicate the death was not a suicide, gunshot residue tests were completed on both Johnson and the rest stop caretaker, he said.
"We gathered forensics and we'll complete a full investigation," Mincks said.


text:
Chieftains open with win
FOSTORIA – It's early as can be in the 2013 season, but Hopewell-Loudon's Bryce Gorrell already is in midseason form.
The Chieftains standout shot a 35 at Loudon Meadows on Tuesday, leading the Chieftains to a victory over St. Wendelin and St. Joe.
H-L finished with 177, 18 strokes better than the Mohawks. The Streaks finished with 198.
The Chieftains' Aric Creeger shot a 41, while Jarid Gelinas had a 42.
St. Wendelin was led by Dalton Murray, who had a 46, one stroke better than teammate Gabe Walters. St. Joe's Aaron Burns led his team with a 42.
SE places third in season opener
NORTH BALTIMORE – Four Liberty-Benton players scored 40 or less, and that was more than enough to knock off North Baltimore and Seneca East at Birch Run.
The Eagles were led by Jarid Neiling, who shot a 36, three strokes better than teammate Adam August. Nick Streacker shot a 40, and the team finished at 154.
North Baltimore (183) got 42s from Brock Boyer and Garrett Boyer.
Seneca East (222) was paced by Austin Holmer's 44.
It was the opening match of the season.