Polymorphisms in Toll-Like Receptors 2, 4, and 9 Are Highly Associated with Hearing Loss in Survivors of Bacterial Meningitis

Genetic variation in innate immune response genes contributes to inter-individual differences in disease manifestation and degree of complications upon infection. We recently described an association of single nucleotide polymorphisms (SNPs) in TLR9 with susceptibility to meningococcal meningitis (MM). In this study, we investigate the association of SNPs in multiple pathogen recognition and immune response genes with clinical features that determine severity and outcome (especially hearing loss) of childhood MM and pneumococcal meningitis (PM). Eleven SNPs in seven genes (TLR2, TLR4, TLR9, NOD1, NOD2, CASP1, and TRAIL) were genotyped in 393 survivors of childhood bacterial meningitis (BM) (327 MM patients and 66 PM patients). Genotype distributions of single SNPs and combination of SNPs were compared between thirteen clinical characteristics associated with severity of BM. After correction for multiple testing, TLR4+896 mutant alleles were highly associated with post-meningitis hearing loss, especially MM (p  = 0.001, OR 4.0 for BM, p  = 0.0004, OR 6.2 for MM). In a multigene analysis, combined carriership of the TLR2+2477 wild type (WT) with TLR4+896 mutant alleles increases the risk of hearing loss (p<0.0001, OR 5.7 in BM and p  = 0.0001, OR 7.6 in MM). Carriage of one or both mutant alleles in TLR4+896 and TLR9 -1237 increases the risk for hearing loss (p  = 0.0006, OR 4.1 in BM). SNPs in immune response genes contribute to differences in clinical severity and outcome of BM. The TLR system seems to play an important role in the immune response to BM and subsequent neuronal damage as well as in cochlear inflammation. Genetic markers may be used for identification of high-risk patients by creating prediction rules for post-meningitis hearing loss and other sequelae, and provide more insight in the complex immune response in the CNS possibly resulting in new therapeutic interventions

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Tandem mass spectrometry: A primer

Tandem mass spectrometry (MS/MS) employs two stages of mass analysis in order to examine selectively the fragmentation of particular ions in a mixture of ions. The various types of instruments which can be used to perform this experiment are described, including those based on separation of the mass-analysis events in time and those based on measurements in physically separate analysers. The several MS/MS scan types-product scans, precursor scans and neutral loss scans-are presented and examples of their applications are provided. These include the characterization of individual compounds and the recognition of groups of compounds with specified functional groups. Applications are shown to the determination of compounds present in complex mixtures. The improvement in signal-to-noise ratio achieved by MS/MS when compounds are ionized by methods which produce high chemical noise is illustrated for choline derivatives. Fundamental aspects of collisional activation in the low and high collision energy range are reviewed

Stabilité des alpha (p, N-Diméthylamino-phényl) imino benzoyl-acétanilides.

(Docteur en Sciences) -- Université catholique de Louvain, 196

[Past and future in an original University: The Catholic University of Louvain]

Created in an university founded in 1425, the chemistry will develop from the XVIIth century, starting in the faculty of medicine. The existence of a chemistry department as such date back to the XIXth century, when the doctorate in science (PhD) is created. A strong cooperation with industry starts from the 50's. Around 1970, the French speaking part of the university, located in the Flemish speaking part of the country, will move to the Walloon part of Belgium. This is the opportunity to create a new town, Louvain-la-Neuve (literally Louvain the new), associated to the University and to an important industrial park. The chemistry department will develop from then, continuing his now traditional cooperation with the industry. The future will depend on the replacement of the present staff by young colleagues. It has started very well, and will be continued at an accelerated pace in the next ten years

Observation of alkali-metal-carboxylate radical anions in fast-atom bombardment

The existence of a series of 32 molecular radical anions from carboxylic acids salts RCOOCat(-.); where R = CH3, CH3CH2, CH3CH2CH2, (CH3)(2)CH, C6H5, o-CH3-C6H4, m-CH3-C6H(4), and p-CH3-C6H4 and Cat = Li, Na, K, Rb, has been proven by the observation of their fragmentation in negative-ion fast-atom bombardment tandem mass spectrometry. These species occur at very low abundance and are not detected in the fast-atom bombardment spectra because they are hidden in the background. However, the collision-induced dissociation fragmentation of ions selected at the mass-to-charge ratio values that correspond to these species display characteristic signals that are completely different from the signals observed from pure matrix or after addition of corresponding metal hydroxide to the matrix. The main fragmentation observed is the loss of the neutral metal atom from RCOOCat(-), followed by a loss of CO2 for the aromatic compounds. Neutral loss experiments also confirm the existence of these radical anions. Scans for the loss of a selected metal after addition of one of the carboxylic acid salts to the matrix display abundant peaks at mass-to-charge ratio values that correspond to the salt radical anions. Some weaker peaks appear at other mass-to-charge ratio values independent of the salt that is used and also are observed from the matrix when the corresponding metal hydroxide is added. When alkali metal salts from some deuterated acids are analyzed, the predicted shifts are observed. The loss of the neutral metal is more pronounced from RCOONa(-.), RCOOK(-.), and RCOORb(-.) than from RCOOLi(-.)

Mass spectrometric analysis of prenyl phosphates and their glycosylated forms.

Three different mass spectrometric method suitable for the analysis of polyprenyl and dolichyl phosphates and their glycosylated forms are described. Fast atom bombardment mass spectrometry (FAB MS) of glycosyl monophosphopolyprenols produces negative ions characteristic of the intact molecule. Tandem mass spectrometry of (M-H)- anions allows the determination of masses of both glycosyl and lipid moieties. Thus, for example, FAB-MS/MS of a mixture of native glycosyl monophosphopolyprenols isolated from ethambutol-treated Mycobacterium smegmatis enabled us to detect two novel pentosyl monophosphopolyprenols. Two other methods are proposed for the analysis of prenyl phosphates, as these compounds do not produce fragments in FAB-MS/MS at low collisional energy. By Desorption Electron Impact ionization (DEI) an intense (M-H3PO4)+ ion as well as fragments corresponding to the successive loss of isoprene residues (68 Da) can be observed. Alternatively, Desorption Chemical Ionization yields ions corresponding to the loss of 66, 78 and 98 Da (i.e. of a part or the entire phosphate moiety) of a prenyl phosphate molecule. Tandem mass spectrometry of the (M-H-98)- ion gives a series of intense fragments differing by 68 mass units over the whole mass range

Fast-atom-bombardment Tandem Mass-spectrometric Analysis of Hydroxamate Siderophores

This paper reports a study of the fast atom bombardment (FAB) tandem mass spectrometric analysis of six trihydroxamate siderophores as the free ligand or as iron complexes in several matrixes. It demonstrates that the [M + H - 53]+ and [M + H - 16]+ ions always detected in the FAB spectra are not fragments, but for the first the free ligand resulting from a decomplexation in the matrix, and for the second a reduction product. The tandem mass spectrometric study of the fragmentation shows that the main fragments result from the break of either peptide or hydroxamate C-N bonds, or (when present) of an ester linkage. When the iron is present in the complex, the heterolytic break of the hydroxamate-iron bond creates a positive charge on the iron, and a negative charge on the hydroxamate group. This causes positive fragments of the free ligand to become corresponding neutrals in the complex, and inversely, when a hydroxamate bond is broken. As the free ligand pseudo-molecular ion is always present in the FAB spectra of the complex, this feature is useful for structural elucidation. Iron has an Fe-54 isotope representing 6.35% of the Fe-56 isotope. This allows identification of iron complexes by a comparison of the daughter spectra of both isotopic pseudo-molecualr ions. As most of the positive fragments in the daughter spectra contain iron, they are shifted two mass units lower by the presence of Fe-54. No fragments or neutral losses typical of all the siderophores were identified, and thus there is no selective scan mode for this compound class. Unambiguous identification of the pseudo-molecular ion of siderophore iron complexes can be achieved by the presence in the FAB spectrum of the free ligand, the reduction product and the iron isotopic peak. Clear confirmation can be obtained by a comparison of the daughter spectra of these ions