Defective complement control of factor H ( y402h ) and FHL 1 in age related macular degeneration. (2007 May)
defective complement control of factor H ( y402h ) and FHL 1 in age related macular degeneration . The common variant in the human complement factor H gene ( CFH ) , with tyr402his , is linked to age related macular degeneration ( AMD ) , a prevalent disorder leading to visual impairment and irreversible blindness in elderly patients . Here we show that the risk variant CFH 402his displays reduced binding to C reactive protein ( CRP ) , heparin and retinal pigment epithelial cells . This reduced binding can cause inefficient complement regulation at the cell surface , particularly when CRP is recruited to injured sites and tissue . In addition , we identify the factor H like protein 1 ( FHL 1 ) , an alternative splice product of the CFH gene as an additional protein that includes the risk residue 402 , and thus confers risk for AMD . FHL 1 is expressed in the eye and the FHL 1 402his risk variant shows similar reduced cell binding and likely reduced complement regulatory functions on the cell surface . CFH and FHL 1 may act in concert in the eye and the reduced surface binding may result in inappropriate local complement control , which in turn can lead to inflammation , disturbance of local physiological homeostasis and progression to cell damage . As a consequence , these processes may lead to AMD pathogenesis .

C3 r102g polymorphism increases risk of age related macular degeneration. (2008 Jun)
C3 r102g polymorphism increases risk of age related macular degeneration . inflammation has long been suspected to play a role in the pathogenesis of age related macular degeneration ( AMD ) . association of variants in the complement factor H ( CFH ) and complement factor B ( CFB ) genes has targeted the search for additional loci to the alternative complement cascade , of which C3 is a major component . Two non synonymous coding polymorphisms within C3 , r102g and l314p , have previously been strongly associated with increased risk . these variants are in strong linkage disequilibrium ( LD ) , making the contribution of this locus to AMD even more difficult to ascertain . We sought to determine whether the C3 association resulted primarily from only one of these two variants or from a combined effect of both in 223 families and an independent dataset of 701 cases and 286 unrelated controls . The C3 polymorphisms were in strong LD ( r ( 2 ) 0 . 85 ) , and both were associated in the family based and case control datasets ( r102g genopdt P 0 . 02 , case control genotypic P 0 . 004 ; l314p genopdt P 0 . 001 , case control genotypic P 0 . 04 ) . In conditional analyses in the case control dataset , r102g remained associated with disease in the l314p risk allele carriers ( P 0 . 01 ) , but there was no effect …

Helicobacter pylori eradication decreases the expression of glycosylphosphatidylinositol anchored complement regulators , decay accelerating factor and homologous restriction factor 20 … (2005 Aug)
helicobacter pylori eradication decreases the expression of glycosylphosphatidylinositol anchored complement regulators , decay accelerating factor and homologous restriction factor 20 , in human gastric epithelium . background : It has previously been reported that there is a strong correlation between the expression of glycosylphosphatidylinositol ( GPI ) anchored complement membrane inhibitor in gastric epithelium and the severity of inflammation of gastric mucosa . To investigate the regulation of complement activity in gastric epithelium during helicobacter pylori ( H . pylori ) associated gastritis , the expression of GPI anchored complement membrane inhibitors , decay accelerating factor ( DAF ) and 20 kDa homologous restriction factor 20 ( hrf20 ) , and membrane cofactor protein ( MCP ) , which is a transmembrane protein , were evaluated after removal of the H . pylori stimulus . furthermore , the expression of the complement fragment , C3c , was also investigated . methods : forty six patients with epigastric symptoms and endoscopically confirmed peptic ulcer or gastritis who had H . pylori infection of the gastric mucosa were enrolled in the present study . biopsy specimens were obtained from the gastric antrum and corpus 1 month before and after eradication . helicobacter pylori infection was determined by the rapid urease test , histology , and culture before eradication , and by histology , culture , and urea breath test after eradication . gastric biopsy specimens obtained before and after eradication were evaluated for infiltration by neutrophils and mononuclear cells . The expression …

Inhibition of complement factor C5 protects against renal ischemia reperfusion injury : inhibition of late apoptosis and inflammation. (2003 Feb)
inhibition of complement factor C5 protects against renal ischemia reperfusion injury : inhibition of late apoptosis and inflammation . background : complement has been implicated in the pathophysiology of renal ischemia reperfusion ( I / R ) injury . however , the mechanism underlying complement mediated renal I / R injury is thus far unknown . To investigate the involvement of complement in I / R injury , we studied the activation and deposition of complement in a murine model of renal I / R injury . furthermore , we examined the effect of inhibition of complement factor C5 on renal I / R injury . methods : Mice were subjected to 45 min of unilateral ischemia and subsequent contralateral nephrectomy and reperfusion for 2 , 12 , or 24 hr . Mice were control treated or treated with BB5 . 1 , a monoclonal antibody that prevents cleavage of complement factor C5 , thereby preventing C5a generation and formation of the membrane attack complex ( MAC ) . results : renal I / R induced extensive deposition of C3 early after reperfusion , whereas C6 and C9 deposition ( MAC formation ) occurred relatively late . I / R induced complement deposition was mainly localized to tubular epithelium . treatment with BB5 . 1 totally prevented MAC formation but also reduced C3 deposition . inhibition of C5 strongly inhibited late inflammation , as measured by neutrophil influx and induction of the murine CXC chemokines macrophage inflammatory protein 2 , …

Selection of GM2 , fucosyl GM1 , globo H and polysialic acid as targets on small cell lung cancers for … (2005 Aug)
selection of GM2 , fucosyl GM1 , globo H and polysialic acid as targets on small cell lung cancers for antibody mediated immunotherapy . glycolipids GM2 , GD2 , GD3 , fucosyl GM1 , sialyl lewis a ( sLe ( a ) ) and globo H , and polysialic acid on embryonal NCAM , are cell surface antigens expressed on small cell lung cancer ( SCLC ) biopsy specimens . They are all candidates for inclusion in a polyvalent , antibody inducing vaccine or for adoptive therapy with monoclonal antibodies ( mAbs ) against SCLC . To identify the minimum optimal combination of target antigens on SCLC and to confirm that antibodies against this combination might be able to mediate complement activation and lysis in the majority of cases , we tested ten SCLC cell lines with fluorescence activated cell sorter ( FACS ) and complement dependent cytotoxicity ( CDC ) assays using mAbs against these seven target antigens individually or pooled in different combinations . We find that ( 1 ) none of these mAbs demonstrated strong FACS reactivity with more than 6 of the 10 cell lines , ( 2 ) no mAb had strong CDC reactivity with more than 4 of the cell lines , ( 3 ) when the mAbs were pooled , nine cell lines were strongly positive by FACS and nine cell lines were strongly positive by CDC , and ( 4 ) mAbs against GM2 , fucgm1 , globo H and polysialic acid …

Complement factor h polymorphism , inflammatory mediators , and retinal vessel diameters : the rotterdam study. (2007 Jun)
complement factor h polymorphism , inflammatory mediators , and retinal vessel diameters : the rotterdam study . purpose : retinal venular dilatation is associated with systemic inflammation . The hypothesis for the current study was that larger retinal venular diameters are related to the His allele of the tyr402his polymorphism in the complement factor H ( CFH ) gene , a major inhibitor of the complement pathway . possible effect modification by smoking and inflammatory markers was examined . methods : This cross sectional study was performed within the rotterdam study , a population based study among elderly persons aged 55 years and older . The tyr402his polymorphism of the CFH gene was genotyped in 5066 participants and retinal arteriolar and venular diameters were graded on digitized fundus transparencies . results : genotype frequencies were 41 in tyrtyr , 45 in tyrhis , and 14 in hishis carriers . The His ( 402 ) allele was associated with smaller rather than larger venular diameters ( age and sex adjusted means and standard errors in micrometers were 222 . 5 / 0 . 45 for tyrtyr , 221 . 9 / 0 . 43 for tyrhis , and 220 . 6 / 0 . 78 for hishis carriers ; P trend 0 . 03 ) . This association was apparent only in never smokers and was not modified by the inflammatory markers erythrocyte sedimentation rate , leukocyte count , C reactive protein , or fibrinogen . adjustment for cardiovascular risk factors …

Eliminating complement factor D reduces photoreceptor susceptibility to light induced damage. (2007 Oct)
eliminating complement factor D reduces photoreceptor susceptibility to light induced damage . purpose : genetic risk factors such as variations in complement factors H ( CFH ) and B ( CFB ) have been implicated in the etiology of age related macular degeneration . It has been hypothesized that inadequate control of complement driven inflammation may be a major factor in disease pathogenesis . The authors tested the involvement of the complement system in an experimental model for oxidative stress mediated photoreceptor degeneration , the light damage mouse model . methods : changes in gene expression were assessed in BALB / c retinas in response to constant light ( CL ) exposure using microarrays and real time PCR . susceptibility to CL exposure was tested in CFD ( / ) mice on a BALB / c background . Eyes were analyzed using electrophysiologic and histologic techniques . results : genes encoding for proteins involved in complement activation were significantly upregulated after CL . The altered gene profiles were similar to proteins accumulated in drusen and to genes identified in the retina and RPE / choroid of patients with age related macular degeneration . cyclic light reared CFD ( / ) and CFD ( / ) mice had indistinguishable rod function and number ; however , after CL challenge , CFD ( / ) photoreceptors were significantly protected . conclusions : these results suggest that rod degeneration in the CL damaged retina involves the activity of the alternative complement pathway and …

Identification of human complement factor H as a ligand for L selectin. (1999 Sep)
identification of human complement factor H as a ligand for L selectin . The selectin family of adhesion molecules ( E , P and L selectins ) is involved in leukocyte recruitment to sites of inflammation and tissue damage . recently it has been shown that L selectin is involved not only in leukocyte tethering and rolling , but also plays an important role in leukocyte activation . For example , glycosylation dependent cell adhesion molecule 1 ( glycam 1 ) , a known ligand for L selectin , has been shown to enhance beta2 integrin function . glycam 1 is a secreted protein and is present in mouse serum at a concentration of approx . 1 . 5 microg / ml . there is no obvious glycam 1 homologue in man and , to date , L selectin ligand ( s ) from human serum have not been characterized . therefore we have used L selectin affinity chromatography , followed by ion exchange chromatography , to isolate specific ligand ( s ) for L selectin . using this procedure , we have isolated three major glycoproteins of apparent molecular masses 170 kDa , 70kda and 50 kDa . The 170 kDa protein band was digested with trypsin and peptides were analysed by delayed extraction matrix assisted laser desorption ionization MS and protein database searching . The 170 kDa protein was identified as the human complement protein factor H . human factor H , isolated by a different method , …

Complement components , regulators and receptors are produced by human monocyte derived dendritic cells. (2007 Apr)
complement components , regulators and receptors are produced by human monocyte derived dendritic cells . complement and dendritic cells ( DCs ) are essential components of innate immunity . Both participate in local inflammation and moreover have roles in the initiation of the acquired immunity response and in the maintenance of tolerance . recent studies have demonstrated the ability of DCs to synthesize C1q , C3 , factor I , factor B and complement receptors 3 and 4 . In this study , we demonstrate that human DCs are a source of other soluble complement proteins including C1q , C4b binding protein ( C4BP ) , C7 and C8 . complement receptors ( CR ) 1 and the CD18 chain ( common for CR3 and CR4 ) were also present on DCs while CR2 was not detected .

Complement factor H polymorphism , complement activators , and risk of age related macular degeneration. (2006 Jul)
complement factor H polymorphism , complement activators , and risk of age related macular degeneration . context : The evidence that inflammation is an important pathway in age related macular degeneration ( AMD ) is growing . recent case control studies demonstrated an association between the complement factor H ( CFH ) gene , a regulator of complement , and AMD . objectives : To assess the associations between the CFH gene and AMD in the general population and to investigate the modifying effect of smoking , serum inflammatory markers , and genetic variation of C reactive protein ( CRP ) . design , setting , AND participants : population based , prospective cohort study of individuals aged 55 years or older ( enrollment between march 20 , 1990 , and July 31 , 1993 , and 3 follow up examinations that were performed between september 1 , 1993 , and december 31 , 2004 ) in rotterdam , the netherlands . The CFH y402h polymorphism was determined in a total of 5681 individuals . information on smoking , erythrocyte sedimentation rate , CRP serum levels , and haplotypes of the CRP gene were assessed at baseline . MAIN outcome measures : All severity stages of prevalent and incident AMD , graded according to the international classification and grading system for AMD . results : The frequency of CFH y402h was 36 . 2 ( 4116 / 11 , 362 alleles ) . At baseline , there were 2062 persons …

Role for complement in development of helicobacter induced gastritis in interleukin 10 deficient mice. (2003 Nov)
Role for complement in development of helicobacter induced gastritis in interleukin 10 deficient mice . The mechanisms by which the immune response can eradicate gastric helicobacter infection are unknown . We hypothesized that helicobacter induced activation of the complement system could promote both inflammation and eradication of helicobacter from the stomach . In vitro studies demonstrated that helicobacter felis activates complement in normal mouse serum but not in serum from Rag2 ( / ) mice , indicating that H . felis activates complement through the classical pathway . Next , we infected complement depleted wild type control and interleukin 10 deficient ( IL 10 ( / ) ) mice with H . felis . helicobacter infection of wild type mice elicited a mild , focal gastritis and did not alter serum complement levels . infection of IL 10 ( / ) mice with H . felis elicited severe gastritis . after the initial colonization , the IL 10 ( / ) mice completely cleared helicobacter from the stomach by day 8 . In contrast to wild type mice , H . felis infected IL 10 ( / ) mice had a marked increase in serum complement levels . complement depletion of wild type mice did not affect the intensity of gastric inflammation or the extent of helicobacter colonization compared to that for the wild type control mice . In contrast , complement depletion of helicobacter infected IL 10 ( / ) mice decreased the severity of gastritis , decreased the …

C5 chemotactic fragment induces leukocyte production of tissue factor activity : a link between complement and coagulation. (1979 Apr)
C5 chemotactic fragment induces leukocyte production of tissue factor activity : a link between complement and coagulation . complement activated human plasma causes generation of tissue factor in human leukocytes . This phenomenon appears to be related to the fifth component of complement ( C5 ) as demonstrated by the use of C5 deficient plasma and suppression of activity with antibody to C5 . isolation of the chemotactic factor from activated serum or trypsinization of purified C5 reproduces the phenomenon . these data provide evidence for a direct link between complement products and activation of the coagulation system . because chemotactic peptides from C5 can be generated by a variety of enzymes , our findings suggest a relationship between complement , coagulation , and inflammation .

Cachectin / tumor necrosis factor regulates hepatic acute phase gene expression. (1986 Nov)
cachectin / tumor necrosis factor regulates hepatic acute phase gene expression . The monokine , cachectin / tumor necrosis factor ( TNF ) differs from interleukin 1 ( IL 1 ) in primary structure and in recognition by a distinct cellular receptor . It does , however , encode effector functions that are similar to those of IL 1 and characteristic of the host response to inflammation or tissue injury . accordingly , we examined the possibility that recombinant generated human TNF regulates hepatic acute phase gene expression . In picomolar concentrations , TNF mediated reversible , dose and time dependent increases in biosynthesis of complement proteins factor B and C3 , alpha 1 antichymotrypsin , and decreases in biosynthesis of albumin and transferrin in human hepatoma cell lines ( Hep G2 , Hep 3B ) . biosynthesis of complement proteins C2 and C4 , and alpha 1 proteinase inhibitor were not affected by TNF . TNF also increased factor B gene expression , but had no effect on C2 gene expression , in murine fibroblasts transfected with cosmid DNA bearing the human C2 and factor B genes . The effect of TNF on acute phase protein expression ( C3 , factor B , albumin ) was pre translational as shown by changes in specific messenger RNA content .

Antiinflammatory effects of polypeptide growth factors. (1990 May)
antiinflammatory effects of polypeptide growth factors . platelet derived growth factor , epidermal growth factor , and fibroblast growth factor inhibit the cytokine induced expression of the alternative complement pathway activator factor B in human fibroblasts . The synthesis of complement components in human fibroblasts is modulated by mediators of inflammation such as cytokines . In particular , interleukin 1 ( IL 1 ) and tumor necrosis factor ( TNF ) induce time and dose dependent increases in the synthesis of complement proteins factor B ( FB ) , C3 , and factor H ( FH ) . polypeptide growth factors are also soluble mediators released during inflammation and able to modulate many fibroblast functions . We have studied the effects of polypeptide growth factors platelet derived growth factor ( PDGF ) , epidermal growth factor ( EGF ) , and fibroblast growth factor ( FGF ) on the synthesis of complement proteins in cultured human fibroblasts . PDGF , EGF , and FGF alone did not affect the level of synthesis of any of the complement proteins analyzed , but simultaneous incubation of PDGF , EGF , or FGF with IL 1 and TNF resulted in a dose dependent inhibition of the cytokine enhanced expression of FB . inhibition of FB synthesis was observed between 4 and 8 h of exposure to PDGF and persisted for 4 h after the removal of the growth factor . analysis of steady state levels of specific FB mRNA suggested that PDGF induced …

The complement system plays a critical role in the development of experimental autoimmune anterior uveitis. (2006 Feb)
The complement system plays a critical role in the development of experimental autoimmune anterior uveitis . purpose : The role of complement in ocular autoimmunity was explored in a experimental autoimmune anterior uveitis ( EAAU ) animal model . methods : EAAU was induced in lewis rats by immunization with bovine melanin associated antigen . complement activation in the eye was monitored by western blot for iC3b . The importance of complement to the development of EAAU was studied by comparing the course of intraocular inflammation in normal lewis rats ( complement sufficient ) with cobra venom factor treated rats ( complement depleted ) . Eyes were harvested from both complement sufficient and complement depleted rats for mRNA and protein analysis for IFN gamma , IL 10 , and interferon inducible protein ( IP ) 10 . intracellular adhesion molecule ( ICAM ) 1 and leukocyte endothelial cell adhesion molecule ( lecam ) 1 were detected by immunofluorescent staining . OX 42 was used to investigate the importance of iC3b and CR3 interaction in EAAU . results : there was a correlation between ocular complement activation and disease progression in EAAU . The incidence , duration , and severity of disease were dramatically reduced after active immunization in complement depleted rats . complement depletion also completely suppressed adoptive transfer EAAU . The presence of complement was critical for local production of cytokines ( IFN gamma and IL 10 ) , chemokines ( IP 10 ) , and adhesion molecules ( …

Hemolytic uremic syndrome : a factor H mutation ( e1172stop ) causes defective complement control at the surface of endothelial … (2007 Jan)
hemolytic uremic syndrome : a factor H mutation ( e1172stop ) causes defective complement control at the surface of endothelial cells . defective complement regulation results in hemolytic uremic syndrome ( HUS ) , a disease that is characterized by microangiopathy , thrombocytopenia , and acute renal failure and that causes endothelial cell damage . For characterization of how defective complement regulation relates to the pathophysiology , the role of the complement regulator factor H and also of a mutant factor H protein was studied on the surface of human umbilical vein endothelial cells . The mutant 145 kD factor H protein was purified to homogeneity , from plasma of a patient with HUS , who is heterozygous for a factor H gene mutation g3587t , which introduces a stop codon at position 1172 . functional analyses show that the lack of the most C terminal domain short consensus repeats 20 severely affected recognition functions ( i . e . , binding to heparin , C3b , C3d , and the surface of endothelial cells ) . Wild type factor H as well as the mutant protein formed dimers in solution as shown by cross linking studies and mass spectroscopy . When assayed in fluid phase , the complement regulatory activity of the mutant protein was normal and comparable to wild type factor H . however , on the surface of endothelial cells , the mutant factor H protein showed severely reduced regulatory activities and lacked protective functions . similarly …

Chemotactic factor inactivation by the myeloperoxidase hydrogen peroxide halide system. (1979 Nov)
chemotactic factor inactivation by the myeloperoxidase hydrogen peroxide halide system . polymorphonuclear leukocytes may modulate the acute inflammatory response by the secretion of enzymes capable of inactivating mediators of inflammation . The ability of the myeloperoxidase H ( 2 ) O ( 2 ) halide system of the neutrophil to inactivate chemoattractants was examined using both a radioassay and a morphologic assay of chemotaxis . incubation of either a complement derived agent , C5a , or a synthetic formyl methionyl peptide chemoattractant with the myeloperoxidase system for 15 min at 37 degrees C resulted in essentially complete loss of chemotactic activity . inactivation was dependent on enzymatically active myeloperoxidase , H ( 2 ) O ( 2 ) or a peroxide generating enzyme system , and a halide cofactor . It was blocked by agents which inhibit peroxidase ( azide ) or degrade H ( 2 ) O ( 2 ) ( catalase ) . inactivation of chemoattractants was time dependent , reaching maximal levels within 1 5 min , and temperature dependent with no significant inactivation occurring at 0 degrees C . H ( 2 ) O ( 2 ) alone had no significant inactivating ability at concentrations as high as 10 mM , whereas in the presence of myeloperoxidase and a halide , 0 . 1 muM H ( 2 ) O ( 2 ) showed significant activity and 10 muM H ( 2 ) O ( 2 ) caused complete inactivation . On a molar basis , …

Inherited complement deficiencies. (1984 Nov)
inherited complement deficiencies . isolated genetic deficiencies of individual components of the complementary system have been described in man for all the components of the classical pathway and the membrane attack complex as well as for factor I , factor H and properdin . It is only for factor B and factor D of the alternative pathway that homozygous deficiency states are not so far known . complement deficiency states provide the most direct way of looking at the role of the complement system in vivo and emphasize the importance of complement in resistance to bacterial infection and in particular to infection with neisseria . This association is not unexpected since in vitro studies have shown complement to be an efficient enhancer of phagocytosis and inflammation . The particularly frequent occurrence of neisserial infection may be ascribed to the ability of these organisms to survive in phagocytic cells so that the plasma cytolytic activity provided by complement is needed to kill them . On the other hand the strong association between complement deficiencies and immune complex diseases especially systemic lupus erythematosus was unexpected and seems paradoxical in view of the large part played by complement in the pathogenesis of immune complex mediated tissue damage . The paradox can be explained in part by the necessity for an intact complement system in the solubilization and the proper handling of immune complexes . It is also likely that complement deficiency can allow the persistence of low virulence organisms that produce disease solely …

Histamine induced cytokine production and ICAM 1 expression in human conjunctival fibroblasts. (2003 Feb)
histamine induced cytokine production and ICAM 1 expression in human conjunctival fibroblasts . purpose : conjunctival fibroblasts stimulated with histamine ( H ) may be directly involved in the inflammatory and remodeling processes of chronic allergic conjunctival diseases . methods : proinflammatory cytokine and growth factor production , and the expression of intercellular adhesion molecule 1 ( ICAM 1 ) were studied in conjunctival fibroblast cultures challenged with different concentrations of H ( from 10 ( 9 ) M to 10 ( ) ( 4 ) M ) . interleukin ( IL ) 1 , IL 4 , IL 6 , IL 8 , tumor necrosis factor alfa ( TNF alpha ) , fibroblast growth factor ( FGF ) , epidermal growth factor ( EGF ) and transforming growth factor beta ( tgfbeta 1 ) were measured in supernatants . ICAM 1 expression was evaluated by a fluorescence activated cell sorter ( FACS ) . inhibitory effects of the H 1 antagonists ( antih ) : emedastine , levocabastine , and azelastine , and of the antih 2 , cimetidine , on H stimulated fibroblasts were evaluated by measuring both cytokines in supernatants and the cellular expression of ICAM 1 . results : histamine increased the production of IL 1 , IL 6 and IL 8 , and ICAM 1 expression . TNF alpha , IL 4 and growth factor production were not modified by histamine . The antih 1 , emedastine , significantly reduced H induced production of IL …

Complement levels and activity in the normal and LPS injured lung. (2007 Mar)
complement levels and activity in the normal and LPS injured lung . complement , a complex protein system , plays an essential role in host defense through bacterial lysis , stimulation of phagocytosis , recruitment of immune cells to infected tissue , and promotion of the inflammatory response . although complement is most well characterized in serum , complement activity is also present in the lung . Here we further characterize the complement system in the normal and inflamed lung . By western blot , C5 , C6 , and factor I were detected in bronchoalveolar lavage ( BAL ) at lower levels than in serum , whereas C2 was detected at similar levels in BAL and serum . C4 binding protein ( C4BP ) was not detectable in BAL . exposure to lipopolysaccharide ( LPS ) elevated levels of C1q , factor B , C2 , C4 , C5 , C6 , and C3 in human BAL and C3 , C5 , and factor B in mouse and rat BAL . message for C1q B , C1r , C1s , C2 , C4 , C3 , C5 , C6 , factor B , and factor H , but not C9 or C4BP , was readily detectable by RT PCR in normal mouse lung . exposure to LPS enhanced factor B expression , decreased C5 expression , and did not affect C1q B expression in mouse and rat lung . BAL from rats exposed to LPS had a greater ability …