Contribution of genome-wide significant single-nucleotide polymorphisms and antiretroviral therapy to dyslipidemia in HIV-infected individuals : a longitudinal study

Rapport de synthèse :Les individus HIV-positifs constituent une population à risque pour les maladies cardiovasculaires telles que |'infarctus cardiaque ou cérébrale. Celles-ci découlent d'une formation accélérée d'athéroscIérose. Ces pathologies s'expliquent en grande partie par une dyslipidémie observée au sein de cette population et qui sont dues à des facteurs externes tels que : l'immunosuppression avancée, la virémie non-contrôlée, et les effets de la thérapie antirétrovirale. Récemment, des polymorphismes nucléotidiques simples (SNP) associés à la dyslipidémie ont été mis en évidence d'une manière globale par des Genome-Wide Association Studies (GWAS). Le but principal de cette étude est d'éva|uer et de valider |'effet cumulatif des SNP identifiés dans ces GWAS pour la dyslipidémie chez des patients HIV-positifs. De plus, |'identification des facteurs non-génétiques qui contribuent à la dyslipidémie démontrent |'importance des facteurs externes, tels que mentionnés ci- dessus, et en particulier à ceux de la thérapie antirétrovirale.Les participants de l'étude proviennent de trois groupes: 426 personnes sélectionnées pour une étude précédente, 222 personnes sélectionnées de façon arbitraire dans la "Cohorte HIV Suisse" et 103 personnes sélectionnées avec un "New-Onset Diabetes mellitus" identifiées lors d'études précédentes. Ces individus ont contribué à plus de 34'000 mesures de lipides sur une durée moyenne supérieure à 7 ans. Pour l'étude, 33 SNP identifiés dans des GWAS et 9 SNP identifiés dans d'autres études publiées dans la littérature non-couverte par des GWAS ont été repris. Le génotypage a été complété pour 745 (99.2%) des 751 participants. Pour les analyses statistiques, les thérapies antirétrovirales ont été divisées en trois groupes (favorisant peu, moyennement et fortement la dyslipidémie), et trois scores génétiques ont été créés (profil favorable, moyennement favorable, non favorable/favorisant la dyslipidémie). Dans un premier temps, l'effet sur la valeur des lipides d'un ou deux allèles variants a été analysé au moyen d'un modèle de régression pour chaque SNP en ajustant le modèle pour les variables non- génétiques. Dans un deuxième temps, les SNP ayant une valeur p >= à 0.2 ont été repris dans un model Multi-SNP, ce modèle est également ajusté pour les variables non-génétiques. Puisque cette étude se base sur des SNP précédemment identifiés, celle-ci évalue uniquement l'association établie entre chaque SNP et les critères qui ont été établis au préalable, tels que : Cholestérol totale, HDL Cholestérol, non-HDL Cholestérol ou Triglycérides. Les résultats trouvés lors de |'étude confirment les résultats de la littérature. Cette étude montre que les SNP associés à la dyslipidémie doivent être analysés dans le contexte d'une thérapie antirétrovirale en tenant compte de la démographie et en considérant les valeurs du HIV (CD4+, virémie). Ces SNP montrent une tendance à prédire une dyslipidémie prolongée chez l'individu. En effet, un patient avec une thérapie antirétrovirale favorisant la dyslipidémie et un patrimoine génétique non-favorable a un risque qui est 3-f0is plus important d'avoir un Non-HDL- Cholestérol élevé, 5-fois plus important d'avoir un HDL-Cholestérol abaissé, et 4 à 5-fois plus important d'avoir une hypertriglycéridémie qu'un patient qui suit une thérapie antirétrovirale favorisant peu la dyslipidémie qui a un patrimoine génétique favorable. Vu la corrélation entre les SNP et la thérapie antirétrovirale, les cliniciens devraient intégrer les informations génétiques afin de choisir une thérapie antirétrovirale en fonction du patrimoine génétique.

Determination of the direct band-gap energy of InAlAs matched to InP by photoluminescence excitation spectroscopy

A series of InxAl1-xAs samples (0.51≪x≪0.55)coherently grown on InP was studied in order to measure the band-gap energy of the lattice matched composition. As the substrate is opaque to the relevant photon energies, a method is developed to calculate the optical absorption coefficient from the photoluminescence excitation spectra. The effect of strain on the band-gap energy has been taken into account. For x=0.532, at 14 K we have obtained Eg0=1549±6 meV

Charge transfer in DNA: hole charge is confined to a single base pair due to solvation effects

We include solvation effects in tight-binding Hamiltonians for hole states in DNA. The corresponding linear-response parameters are derived from accurate estimates of solvation energy calculated for several hole charge distributions in DNA stacks. Two models are considered: (A) the correction to a diagonal Hamiltonian matrix element depends only on the charge localized on the corresponding site and (B) in addition to this term, the reaction field due to adjacent base pairs is accounted for. We show that both schemes give very similar results. The effects of the polar medium on the hole distribution in DNA are studied. We conclude that the effects of polar surroundings essentially suppress charge delocalization in DNA, and hole states in (GC)n sequences are localized on individual guanines

Metallic and nonmetallic shine in luster: An elastic ion backscattering study

Luster is a metal glass nanocomposite layer first produced in the Middle East in early Islamic times ( 9th AD) made of metal copper or silver nanoparticles embedded in a silica-based glassy matrix. These nanoparticles are produced by ion exchange between Cu+ and Ag+ and alkaline ions from the glassy matrix and further growth in a reducing atmosphere. The most striking property of luster is its capability of reflecting light like a continuous metal layer and it was unexpectedly found to be linked to one single production parameter: the presence of lead in the glassy matrix composition. The purpose of this article is to describe the characteristics and differences of the nanoparticle layers developed on lead rich and lead free glasses. Copper luster layers obtained using the ancient recipes and methods are analyzed by means of elastic ion backscattering spectroscopy associated with other analytical techniques. The depth profile of the different elements is determined, showing that the luster layer formed in lead rich glasses is 5–6 times thinner and 3–4 times Cu richer. Therefore, the metal nanoparticles are more densely packed in the layer and this fact is related to its higher reflectivity. It is shown that lead influences the structure of the metal nanoparticle layer through the change of the precipitation kinetics

A Pneumocystis jirovecii pneumonia outbreak in a single kidney-transplant center: role of cytomegalovirus co-infection.

Pneumocystis jirovecii pneumonia (PCP) and cytomegalovirus (CMV) infection represent possible complications of medical immunosuppression. Between 2005 and 2010, non-human immunodeficiency virus (HIV) PCP patients admitted to a nephrology unit were analyzed for outcome, CMV comorbidity, and patient-to-patient contacts prior to PCP. In contrast to 2002-2004 (no cases) and 2008-2010 (10 cases), a PCP outbreak of 29 kidney-transplant recipients and one patient with anti-glomerular basement membrane disease occurred between 2005 and 2007. None of the patients were on PCP chemoprophylaxis. In four PCP patients, the genotyping data of bronchoalveolar lavage specimen showed an identical Pneumocystis strain. PCP cases had a higher incidence of CMV infection (12 of 30 PCP patients) and CMV disease (four patients) when compared to matched PCP-free controls (p < 0.05). Cotrimoxazole and, if applicable, ganciclovir were started 2.0 ± 4.0 days following admission, and immunosuppressive medication was reduced. In-hospital mortality was 10% and the three-year mortality was 20%. CMV co-infection did not affect mortality. CMV co-infection more frequently occurred during a cluster outbreak of non-HIV PCP in comparison to PCP-free controls. Here, CMV awareness and specific therapy of both CMV infection and PCP led to a comparatively favorable patient outcome. The role of patient isolation should be further investigated in incident non-HIV PCP.

Decoding sequence learning from single-trial intracranial EEG in humans.

We propose and validate a multivariate classification algorithm for characterizing changes in human intracranial electroencephalographic data (iEEG) after learning motor sequences. The algorithm is based on a Hidden Markov Model (HMM) that captures spatio-temporal properties of the iEEG at the level of single trials. Continuous intracranial iEEG was acquired during two sessions (one before and one after a night of sleep) in two patients with depth electrodes implanted in several brain areas. They performed a visuomotor sequence (serial reaction time task, SRTT) using the fingers of their non-dominant hand. Our results show that the decoding algorithm correctly classified single iEEG trials from the trained sequence as belonging to either the initial training phase (day 1, before sleep) or a later consolidated phase (day 2, after sleep), whereas it failed to do so for trials belonging to a control condition (pseudo-random sequence). Accurate single-trial classification was achieved by taking advantage of the distributed pattern of neural activity. However, across all the contacts the hippocampus contributed most significantly to the classification accuracy for both patients, and one fronto-striatal contact for one patient. Together, these human intracranial findings demonstrate that a multivariate decoding approach can detect learning-related changes at the level of single-trial iEEG. Because it allows an unbiased identification of brain sites contributing to a behavioral effect (or experimental condition) at the level of single subject, this approach could be usefully applied to assess the neural correlates of other complex cognitive functions in patients implanted with multiple electrodes.

A comparison of dequalinium chloride vaginal tablets (Fluomizin®) and clindamycin vaginal cream in the treatment of bacterial vaginosis: a single-blind, randomized clinical trial of efficacy and safety.

AIMS: To investigate if vaginal application of dequalinium chloride (DQC, Fluomizin®) is as effective as vaginal clindamycin (CLM) in the treatment of bacterial vaginosis (BV). METHODS: This was a multinational, multicenter, single-blind, randomized trial in 15 centers, including 321 women. They were randomized to either vaginal DQC tablets or vaginal CLM cream. Follow-up visits were 1 week and 1 month after treatment. Clinical cure based on Amsel's criteria was the primary outcome. Secondary outcomes were rate of treatment failures and recurrences, incidence of post-treatment vulvovaginal candidosis (VVC), lactobacillary grade (LBG), total symptom score (TSC), and safety. RESULTS: Cure rates with DQC (C1: 81.5%, C2: 79.5%) were as high as with CLM (C1: 78.4%, C2: 77.6%). Thus, the treatment with DQC had equal efficacy as CLM cream. A trend to less common post-treatment VVC in the DQC-treated women was observed (DQC: 2.5%, CLM: 7.7%; p = 0.06). Both treatments were well tolerated with no serious adverse events occurring. CONCLUSION: Vaginal DQC has been shown to be equally effective as CLM cream, to be well tolerated with no systemic safety concerns, and is therefore a valid alternative therapy for women with BV [ClinicalTrials.gov, Med380104, NCT01125410].

Single-dose oral amoxicillin or linezolid for prophylaxis of experimental endocarditis due to vancomycin-susceptible and vancomycin-resistant Enterococcus faecalis.

Endocarditis prophylaxis following genitourinary or gastrointestinal procedures targets Enterococcus faecalis. Prophylaxis recommendations advocate oral amoxicillin (2 g in the United States and 3 g in the United Kingdom) in moderate-risk patients and intravenous amoxicillin (2 g) or vancomycin (1 g) plus gentamicin in high-risk patients. While ampicillin-resistant (or amoxicillin-resistant) E. faecalis is still rare, there is a concern that these regimens might fail against vancomycin-resistant and/or aminoglycoside-resistant isolates. The present study tested oral linezolid as an alternative. Rats with catheter-induced aortic vegetations were given prophylaxis simulating human pharmacokinetics of oral amoxicillin (2- to 3-g single dose), oral linezolid (600 mg, single or multiple oral doses every 12 h), or intravenous vancomycin (1-g single dose). Rats were then inoculated with the minimum inoculum infecting 90% of the animals (90% infective dose [ID(90)]) or with 10 times the ID(90) of the vancomycin-susceptible E. faecalis strain JH2-2 or the vancomycin-resistant (VanA phenotype) E. faecalis strain UCN41. Amoxicillin was also tested with two additional vancomycin-susceptible E. faecalis strains, 309 and 1209. Animals were sacrificed 3 days later. All the tested bacteria were susceptible to amoxicillin and gentamicin. Single-dose amoxicillin provided 100% protection against all four isolates at both the ID(90) and 10 times the ID(90). In contrast, linezolid required up to four consecutive doses to provide full protection against the vancomycin-resistant isolate. Vancomycin protected only against the vancomycin-susceptible strain. The high efficacy of single-dose oral amoxicillin suggests that this regimen could be used for prophylaxis in both moderate-risk and high-risk patients without additional aminoglycosides. Linezolid appears to be less reliable, at least against the vancomycin-resistant strain.

Performance of blood pressure-to-height ratio at a single screening visit for the identification of hypertension in children.

BACKGROUND: The diagnosis of hypertension in children is difficult because of the multiple sex-, age-, and height-specific thresholds to define elevated blood pressure (BP). Blood pressure-to-height ratio (BPHR) has been proposed to facilitate the identification of elevated BP in children. OBJECTIVE: We assessed the performance of BPHR at a single screening visit to identify children with hypertension that is sustained elevated BP. METHOD: In a school-based study conducted in Switzerland, BP was measured at up to three visits in 5207 children. Children had hypertension if BP was elevated at the three visits. Sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) for the identification of hypertension were assessed for different thresholds of BPHR. The ability of BPHR at a single screening visit to discriminate children with and without hypertension was evaluated with receiver operating characteristic (ROC) curve analyses. RESULTS: The prevalence of systolic/diastolic hypertension was 2.2%. Systolic BPHR had a better performance to identify hypertension compared with diastolic BPHR (area under the ROC curve: 0.95 vs. 0.84). The highest performance was obtained with a systolic BPHR threshold set at 0.80 mmHg/cm (sensitivity: 98%; specificity: 85%; PPV: 12%; and NPV: 100%) and a diastolic BPHR threshold set at 0.45 mmHg/cm (sensitivity: 79%; specificity: 70%; PPV: 5%; and NPV: 99%). The PPV was higher among tall or overweight children. CONCLUSION: BPHR at a single screening visit had a high performance to identify hypertension in children, although the low prevalence of hypertension led to a low PPV.

Generation of mouse-induced pluripotent stem cells by transient expression of a single nonviral polycistronic vector

Induced pluripotent stem (iPS) cells have generated keen interestdue to their potential use in regenerative medicine. They havebeen obtained from various cell types of both mice and humans byexogenous delivery of different combinations of Oct4, Sox2, Klf4,c-Myc, Nanog, and Lin28. The delivery of these transcription factorshas mostly entailed the use of integrating viral vectors (retrovirusesor lentiviruses), carrying the risk of both insertional mutagenesisand oncogenesis due to misexpression of these exogenousfactors. Therefore, obtaining iPS cells that do not carry integratedtransgene sequences is an important prerequisite for their eventualtherapeutic use. Here we report the generation of iPS cell linesfrom mouse embryonic fibroblasts with no evidence of integrationof the reprogramming vector in their genome, achieved by nucleofectionof a polycistronic construct coexpressing Oct4, Sox2, Klf4,and c-Myc

Bioreporters: gfp versus lux revisited and single-cell response.

Genetically engineered organisms expressing spectroscopically active reporter molecules in response to chemical effectors display great potential as living transducers in sensing applications. Green fluorescent protein (gfp gene) bioreporters have distinct advantages over luminescent couterparts (lux gene), including applicability at the single-cell level, but are typically less sensitive. Here we describe a gfp-bearing bioreporter that is sensitive to naphthalene (a poorly water soluble pollutant behaving like a large class of hydrophobic compounds), is suitable for use in chemical assays and bioavailability studies, and has detection limits comparable to lux-bearing bioreporters for higher efficiency detection strategies. Simultaneously, we find that the exploitation of population response data from single-cell analysis is not an algorithmic conduit to enhanced signal detection and hence lower effector detection limits, as normally assumed. The assay reported functions to equal effect with or without biocide.

Design and evaluation of a panel os single-nucleotide polymorphisms in microRNA genomic regions for association studies in human disease

MicroRNAs (miRNA) are recognized posttranscriptional gene repressors involved in the control of almost every biological process. Allelic variants in these regions may be an important source of phenotypic diversity and contribute to disease susceptibility. We analyzed the genomic organization of 325 human miRNAs (release 7.1, miRBase) to construct a panel of 768 single-nucleotide polymorphisms (SNPs) covering approximately 1 Mb of genomic DNA, including 131 isolated miRNAs (40%) and 194 miRNAs arranged in 48 miRNA clusters, as well as their 5-kb flanking regions. Of these miRNAs, 37% were inside known protein-coding genes, which were significantly associated with biological functions regarding neurological, psychological or nutritional disorders. SNP coverage analysis revealed a lower SNP density in miRNAs compared with the average of the genome, with only 24 SNPs located in the 325 miRNAs studied. Further genotyping of 340 unrelated Spanish individuals showed that more than half of the SNPs in miRNAs were either rare or monomorphic, in agreement with the reported selective constraint on human miRNAs. A comparison of the minor allele frequencies between Spanish and HapMap population samples confirmed the applicability of this SNP panel to the study of complex disorders among the Spanish population, and revealed two miRNA regions, hsa-mir-26a-2 in the CTDSP2 gene and hsa-mir-128-1 in the R3HDM1 gene, showing geographical allelic frequency variation among the four HapMap populations, probably because of differences in natural selection. The designed miRNA SNP panel could help to identify still hidden links between miRNAs and human disease.

Capacity-achieving input covariance for single-user multi-antenna channels

We characterize the capacity-achieving input covariance for multi-antenna channels known instantaneously at the receiver and in distribution at the transmitter. Our characterization, valid for arbitrary numbers of antennas, encompasses both the eigenvectors and the eigenvalues. The eigenvectors are found for zero-mean channels with arbitrary fading profiles and a wide range of correlation and keyhole structures. For the eigenvalues, in turn, we present necessary and sufficient conditions as well as an iterative algorithm that exhibits remarkable properties: universal applicability, robustness and rapid convergence. In addition, we identify channel structures for which an isotropic input achieves capacity.

State of Iowa, Single Audit Report, Independent Auditor's Reports, Iowa Comprehensive Annual Financial Report - Financial Section, Schedule of Expenditures of Federal Awards, Schedule of Findings and Questioned Costs, June 30, 2004

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