19 research outputs found
Lipid A structure and immunoinhibitory effect of the marine bacterium Cobetia pacifica KMM 3879T
No full textThe structural elucidation of lipopolysaccharides (LPSs) from Gram‐negative marine bacteria, along with the assessment of their immunological properties, is a fascinating and active research field. Such studies can aid understanding of adaptation phenomena that occur in the marine environment, but they can also open up new perspectives on the design and development of new immunoregulatory drugs. In this paper, we report the structural characterization of the lipid A component of the LPS isolated from the marine bacterium Cobetia pacifica KMM 3879T, which is characterized by a family of structures differing in their acylation patterns. The structural assignment was achieved through extensive chemical analysis and matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry. Moreover, cellular immunology studies on the LPS highlighted its low immunostimulatory impact, as well as a very interesting and promising inhibitory activity of the toxic effects of Escherichia coli LPS
Predictive value of cardiac troponin T and I in hemodialysis patients
No full textCardiac troponin T (cTnT) and I (cTnI) levels are considered as important diagnostic tools in acute coronary events. They could be of predictive value in hemodialysis (HD) patients. The aim of this study was to determine the prevalence of increased cTnI and cTnT in HD patients and their prognostic relevance to all-cause mortality. We measured cTnT and cTnI at baseline in 145 asymptomatic HD patients. We used three different cut-off criteria to define elevated cardiac troponin levels as follows: the 99 th percentile of a reference population, the lowest concentration to give a 10% imprecision [10% coefficient of variation (10% CV)] and the relative operating characteristic (ROC) curve-determined value optimized for diagnostic sensitivity and specificity for detection of myocardial injury (MI). These concentrations were 0.01 ng/mL, 0.03 ng/mL and 0.1 ng/mL for cTnT and 0.2 ng/mL, 0.6 ng/mL and 1 ng/mL for cTnI, respectively. Patients were followed for all-cause mortality (median follow-up 551 days). Kaplan-Meier survival curves, log-rank test and Cox models were employed to determine whether baseline cTnT and cTnI levels were predictive of mortality. Greater percentages of patients had an increased cTnT versus cTnI at each cut-off as follows: 99 th percentile, 90.3% versus 35.2%; 10% CV, 73.1% versus 2.1%; and ROC, 20.7% versus 0.7%. During follow-up, 40 patients died. Elevated cTnT levels above the ROC concentration were associated with increased mortality, although it was not significant after adjustment for other risk factors. Univariate and adjusted hazard ratios were 2.3 [confidence intervals (CI), 1.2-4.5; P = 0. 01] and 1.9 (CI, 0.9-3.9; P = 0.07). No differences were found for cTnI levels. Diabetes mellitus was also an independent predictor of mortality. There is a high prevalence of positive cTnT and cTnI in asymptomatic HD patients, with a greater number of patients having an increased cTnT. Elevated troponin T, but not cTnI, seems to be associated with poor prognosis
Epidemiology of hemodialysis patients in Aleppo city
No full textTo determine the characteristics of the hemodialysis (HD) patients in Aleppo city, we surveyed the hospitals representing the main dialysis centers in the city including private and community facilities during 2006. Personal patients′ interviews and hospitals records were the source of data. The total number of patients in 2006 undergoing HD was 550 patients; 280 (50.9%) were males, and the age ranged from 5-82 years with mean and median age 44.7 and 45 years, respectively. The incidence (IR) and prevalence rate (PR) for hemodialysis were 60 pmp and 226 pmp, respectively. The major primary renal diseases in the end-stage renal disease (ESRD) patients included hypertension (HTN), glomerulonephritis (GN), and diabetes mellitus (DM), 21.1%, 20.5 %, and 19.45, respectively. The percent of Anti-HCV, HBV hepatitis and HBV vaccine were 54.4%, 7.8%, and 52.9%, respectively. This study suggests that the IR of hemodialysis was relatively low due to the high cost of treatment, and the PR for hemodialysis was also relatively low may be due to high mortality rate and low kidney transplantation rate in this country. There was an equal percentage of both genders in the hemodialysis population
Comparison of lipopolysaccharide structures of Bordetella pertussis clinical isolates from pre- and post-vaccine era
No full textEndotoxins are lipopolysaccharides (LPS), and major constituents of the outer membrane of Gram-negative bacteria. Bordetella pertussis LPS were the only major antigens, of this agent of whooping-cough, that were not yet analyzed on isolates from the pre- and post-vaccination era. We compared here the LPS structures of four clinical isolates with that of the vaccine strain BP 1414. All physico-chemical analyses, including SDS-PAGE, TLC, and different MALDI mass spectrometry approaches were convergent. They helped demonstrating that, on the contrary to some other B. pertussis major antigens, no modification occurred in the dodecasaccharide core structure, as well as in the whole LPS molecules. These results are rendering these major antigens good potential vaccine components. Molecular modeling of this conserved LPS structure also confirmed the conclusions of previous experiments leading to the production of anti-LPS monoclonal antibodies and defining the main epitopes of these major antigens. \ua9 2013 Elsevier Ltd.Peer reviewed: YesNRC publication: Ye
Minor modifications to the phosphate groups and the C3' acyl chain length of lipid A in two Bordetella pertussis strains, BP338 and 18-323, independently affect toll-like receptor 4 protein activation
No full textInternational audienceLipopolysaccharides (LPS) of Bordetella pertussis are important modulators of the immune system. Interaction of the lipid A region of LPS with the Toll-like receptor 4 (TLR4) complex causes dimerization of TLR4 and activation of downstream nuclear factor κB (NFκB), which can lead to inflammation. We have previously shown that two strains of B. pertussis, BP338 (a Tohama I-derivative) and 18-323, display two differences in lipid A structure. 1) BP338 can modify the 1- and 4'-phosphates by the addition of glucosamine (GlcN), whereas 18-323 cannot, and 2) the C3' acyl chain in BP338 is 14 carbons long, but only 10 or 12 carbons long in 18-323. In addition, BP338 lipid A can activate TLR4 to a greater extent than 18-323 lipid A. Here we set out to determine the genetic reasons for the differences in these lipid A structures and the contribution of each structural difference to the ability of lipid A to activate TLR4. We show that three genes of the lipid A GlcN modification (Lgm) locus, lgmA, lgmB, and lgmC (previously locus tags BP0399-BP0397), are required for GlcN modification and a single amino acid difference in LpxA is responsible for the difference in C3' acyl chain length. Furthermore, by introducing lipid A-modifying genes into 18-323 to generate isogenic strains with varying penta-acyl lipid A structures, we determined that both modifications increase TLR4 activation, although the GlcN modification plays a dominant role. These results shed light on how TLR4 may interact with penta-acyl lipid A species
Bordetella holmesii: Lipid A Structures and Corresponding Genomic Sequences Comparison in Three Clinical Isolates and the Reference Strain ATCC 51541
No full textInternational audienceBordetella holmesii can cause invasive infections but can also be isolated from the respiratory tract of patients with whooping-cough like symptoms. For the first time, we describe the lipid A structure of B. holmesii reference strain ATCC 51541 (alias NCTC12912 or CIP104394) and those of three French B. holmesii clinical isolates originating from blood (Bho1) or from respiratory samples (FR4020 and FR4101). They were investigated using chemical analyses, gas chromatography-mass spectrometry (GC-MS), and matrix-assisted laser desorption ionization-mass spectrometry (MALDI-MS). The analyses revealed a common bisphosphorylated β-(1→6)-linked d-glucosamine disaccharide with hydroxytetradecanoic acid in amide linkages. Similar to B. avium, B. hinzii and B. trematum lipids A, the hydroxytetradecanoic acid at the C-2' position are carrying in secondary linkage a 2-hydroxytetradecanoic acid residue resulting of post-traductional biosynthesis modifications. The three clinical isolates displayed characteristic structural traits compared to the ATCC 51541 reference strain: the lipid A phosphate groups are more or less modified with glucosamine in the isolates and reference strain, but the presence of 10:0(3-OH) is only observed in the isolates. This trait was only described in B. pertussis and B. parapertussis strains, as well as in B. petrii isolates by the past. The genetic bases for most of the key structural elements of lipid A were analyzed and supported the structural data
Gut Microbiota Ecology and Inferred Functions in Children With ASD Compared to Neurotypical Subjects
No full textAutism spectrum disorders (ASDs) is a multifactorial neurodevelopmental disorder. The communication between the gastrointestinal (GI) tract and the central nervous system seems driven by gut microbiota (GM). Herein, we provide GM profiling, considering GI functional symptoms, neurological impairment, and dietary habits. Forty-one and 35 fecal samples collected from ASD and neurotypical children (CTRLs), respectively, (age range, 3-15 years) were analyzed by 16S targeted-metagenomics (the V3-V4 region) and inflammation and permeability markers (i.e., sIgA, zonulin lysozyme), and then correlated with subjects' metadata. Our ASD cohort was characterized as follows: 30/41 (73%) with GI functional symptoms; 24/41 (58%) picky eaters (PEs), with one or more dietary needs, including 10/41 (24%) with food selectivity (FS); 36/41 (88%) presenting high and medium autism severity symptoms (HMASSs). Among the cohort with GI symptoms, 28/30 (93%) showed HMASSs, 17/30 (57%) were picky eaters and only 8/30 (27%) with food selectivity. The remaining 11/41 (27%) ASDs without GI symptoms that were characterized by HMASS for 8/11 (72%) and 7/11 (63%) were picky eaters. GM ecology was investigated for the overall ASD cohort versus CTRLs; ASDs with GI and without GI, respectively, versus CTRLs; ASD with GI versus ASD without GI; ASDs with HMASS versus low ASSs; PEs versus no-PEs; and FS versus absence of FS. In particular, the GM of ASDs, compared to CTRLs, was characterized by the increase of Proteobacteria, Bacteroidetes, Rikenellaceae, Pasteurellaceae, Klebsiella, Bacteroides, Roseburia, Lactobacillus, Prevotella, Sutterella, Staphylococcus, and Haemophilus. Moreover, Sutterella, Roseburia and Fusobacterium were associated to ASD with GI symptoms compared to CTRLs. Interestingly, ASD with GI symptoms showed higher value of zonulin and lower levels of lysozyme, which were also characterized by differentially expressed predicted functional pathways. Multiple machine learning models classified correctly 80% overall ASDs, compared with CTRLs, based on Bacteroides, Lactobacillus, Prevotella, Staphylococcus, Sutterella, and Haemophilus features. In conclusion, in our patient cohort, regardless of the evaluation of many factors potentially modulating the GM profile, the major phenotypic determinant affecting the GM was represented by GI hallmarks and patients' age
Antigenic modulation limits the efficacy of anti-CD20 antibodies: implications for antibody selection
No full textRituximab, a monoclonal antibody which targets CD20 on B-cells, is now central to the treatment of a variety of malignant and autoimmune disorders. Despite this success a substantial proportion of B-cell lymphomas are unresponsive or develop resistance, hence more potent anti-CD20 mAb are continually being sought. Here we demonstrate that type II (tositumomab-like) anti-CD20 mAb are 5 times more potent than type I (rituximab-like) reagents in depleting human CD20 Tg B-cells, despite both operating exclusively via activatory FcR-expressing macrophages. Much of this disparity in performance is attributable to type I mAb-mediated internalization of CD20 by B-cells leading to reduced macrophage recruitment and the degradation of CD20:mAb complexes, shortening mAb half-life. Importantly, human B cells from healthy donors, and most cases of Chronic Lymphatic Leukemia (CLL) and Mantle Cell Lymphoma, showed rapid CD20 internalization which paralleled that seen in the Tg mouse B cells, while most Follicular Lymphoma (FL) and Diffuse Large B-Cell Lymphoma (DLBCL) cells were far more resistant to CD20 loss. We postulate that differences in CD20 modulation may play a central role in determining the relative efficacy of rituximab in treating these diseases and strengthen the case for focusing on type II anti-CD20 mAb in the clinic. <br/
The LipidA from Rhodopseudomonas palustris Strain BisA53 LPS Possesses a Unique Structure and Low Immunostimulant Properties
No full textThe search for novel lipid A analogues from any biological source that can act as antagonists, displaying inhibitory activity towards the production of pro-inflammatory cytokines, or as immunomodulators in mammals, is a very topical issue. To this aim, the structure and immunological properties of the lipopolysaccharide lipid A from the purple nonsulfur bacterium Rhodopseudomonas palustris strain BisA53 have been determined. This lipid A displays a unique structural feature, with a non-phosphorylated skeleton made up of the tetrasaccharide Manp-α-(1→4)-GlcpN3N-β-1→6-GlcpN3N-α-(1→1)-α-GalpA, and four primary amide-linked 14:0(3-OH) and, as secondary O-acyl substituents, a 16:0 and the very long-chain fatty acid 26:0(25-OAc), appended on the GlcpN3N units. This lipid A architecture is definitely rare, so far identified only in the genus Bradyrhizobium. Immunological tests on both murine bone-marrow-derived and human monocyte-derived macrophages revealed an extremely low immunostimulant capability of this LPS lipid A
Association between smoking and chronic kidney disease: a case control study
No full textAbstract Background The progression of chronic kidney disease (CKD) remains one of the main challenges in clinical nephrology. Therefore, identifying the pathophysiological mechanisms and the independent preventable risk factors helps in decreasing the number of patients suffering end stage renal disease and slowing its progression. Methods Smoking data was analyzed in patients with CKD throughout 2005-2009. One hundred and ninety-eight patients who had recently been diagnosed with stage three CKD or higher according to the National Kidney Foundation (NKF) 2002 Classification were studied. The control group was randomly selected and then matched with the case subjects using a computerized randomization technique. The relative risk was estimated by computing odds ratio (OR) by using multinomial logistic regression in SPSS ® for Windows between the two groups. Results Smoking significantly increases the risk of CKD (OR = 1.6, p = 0.009, 95% CI = 1.12-2.29). When compared to nonsmokers, current smokers have an increased risk of having CKD (OR = 1.63 p = 0.02, 95% CI = 1.08-2.45), while former smokers did not have a statistically significant difference. The risk increased with high cumulative quantity (OR among smokers with > 30 pack-years was 2.6, p = 0.00, 95% CI = 1.53-4.41). Smoking increased the risk of CKD the most for those classified as hypertensive nephropathy (OR = 2.85, p = 0.01, 95% CI = 1.27-6.39) and diabetic nephropathy (2.24, p = 0.005, 95% CI = 1.27-3.96). No statistically significant difference in risk was found for glomerulonephritis patients or any other causes. Conclusion This study suggests that heavy cigarette smoking increases the risk of CKD overall and particularly for CKD classified as hypertensive nephropathy and diabetic nephropathy.</p
