Safety of intramuscular influenza vaccine in patients receiving oral anticoagulation therapy: a single blinded multi-centre randomized controlled clinical trial

Influenza vaccines are recommended for administration by the intramuscular route. However, many physicians use the subcutaneous route for patients receiving an oral anticoagulant because this route is thought to induce fewer hemorrhagic side effects. Our aim is to assess the safety of intramuscular administration of influenza vaccine in patients on oral anticoagulation therapy. Methods: Design: Randomised, controlled, single blinded, multi-centre clinical trial. Setting: 4 primary care practices in Barcelona, Spain. Participants: 229 patients on oral anticoagulation therapy eligible for influenza vaccine during the 20032004 season. Interventions: intramuscular administration of influença vaccine in the experimental group (129 patients) compared to subcutaneous administration in the control group (100 patients). Primary outcome: change in the circumference of the arm at the site of injection at 24 hours. Secondary outcomes: appearance of local reactions and pain at 24 hours and at 10 days; change in INR (International Normalized Ratio) at 24 hours and at 10 days. Analysis was by intention to treat using the 95% confidence intervals of the proportions or mean differences. Results: Baseline variables in the two groups were similar. No major side effects or major haemorrhage during the follow-up period were reported. No significant differences were observed in the primary outcome between the two groups. The appearance of local adverse reactions was more frequent in the subcutaneous administration group (37,4% vs. 17,4%, 95% confidence interval of the difference 8,2% to 31,8%). Conclusion: This study shows that the intramuscular administration route of influenza vaccine in patients on anticoagulant therapy does not have more side effects than the subcutaneous administration route

Effect of hip flexion angle on hamstring optimum length after a single set of concentric contractions.

The eccentric contraction mode was proposed to be the primary stimulus for optimum angle (angle at which peak torque occurs) shift. However, the training range of motion (or muscle excursion range) could be a stimulus as important. The aim of this study was to assess the influence of the training range of motion stimulus on the hamstring optimum length. It was hypothesised that performing a single set of concentric contractions beyond optimal length (seated at 80° of hip flexion) would lead to an immediate shift of the optimum angle to longer muscle length while performing it below (supine at 0° of hip flexion) would not provide any shift. Eleven male participants were assessed on an isokinetic dynamometer. In both positions, the test consisted of 30 consecutive knee flexions at 4.19 rad · s⁻¹. The optimum angle was significantly shifted by ∼15° in the direction of longer muscle length after the contractions at 80° of hip flexion, while a non-significant shift of 3° was found at 0°. The hamstring fatigability was not influenced by the hip position. It was concluded that the training range of motion seems to be a relevant stimulus for shifting the optimum angle to longer muscle length. Moreover, fatigue appears as a mechanism partly responsible for the observed shift.

The role of auditory cortices in the retrieval of single-trial auditory-visual object memories.

Single-trial encounters with multisensory stimuli affect both memory performance and early-latency brain responses to visual stimuli. Whether and how auditory cortices support memory processes based on single-trial multisensory learning is unknown and may differ qualitatively and quantitatively from comparable processes within visual cortices due to purported differences in memory capacities across the senses. We recorded event-related potentials (ERPs) as healthy adults (n = 18) performed a continuous recognition task in the auditory modality, discriminating initial (new) from repeated (old) sounds of environmental objects. Initial presentations were either unisensory or multisensory; the latter entailed synchronous presentation of a semantically congruent or a meaningless image. Repeated presentations were exclusively auditory, thus differing only according to the context in which the sound was initially encountered. Discrimination abilities (indexed by d') were increased for repeated sounds that were initially encountered with a semantically congruent image versus sounds initially encountered with either a meaningless or no image. Analyses of ERPs within an electrical neuroimaging framework revealed that early stages of auditory processing of repeated sounds were affected by prior single-trial multisensory contexts. These effects followed from significantly reduced activity within a distributed network, including the right superior temporal cortex, suggesting an inverse relationship between brain activity and behavioural outcome on this task. The present findings demonstrate how auditory cortices contribute to long-term effects of multisensory experiences on auditory object discrimination. We propose a new framework for the efficacy of multisensory processes to impact both current multisensory stimulus processing and unisensory discrimination abilities later in time.

Euroopan yhteisen maksualueen (Single European payment area) vaikutukset maksuliikenteen tehokkuuteen case: Metso Oyj

Työn tavoitteena oli tutkia Euroopan yhteisen maksualueen (Single European Payment Area, SEPA) kehitystä ja selvittää mitä hyötyä siitä on Metso-konsernin maksuliikenteelle. Teoreettisessa osassa tarkastellaan mistä tehokas maksuliikenne koostuu ja esitetään SEPA:n kehitys peilaamalla sitä Berger et al.:n (1996) teoriasta muodostettuihin implikaatioihin. Empiirinen osuus sisältää kuvailevan Case-tutkimuksen, joka toteutettiin teemahaastatteluilla. Sitä täydennettiin kvantitatiivisella tilisiirtokustannusaineistolla (Metso-konserni). Tulosten mukaan SEPA-kehitys on sekä positiivista että negatiivista: 1) Jos kaikki maksuliikenteen osapuolet kokevat saavansa hyötyä uudistuksista, toteutuu sosiaalinen tehokkuus, jolloin kehitys nopeutuu ja kustannukset laskevat. Tämä on nähtävissä Metso-konsernin tilisiirtokustannusten kehityksestä. 2) SEPA lisää pankkien kustannuksia. 3) Järjestelmien kehitys vähentää maksuliikenneriskiä 4) Maksualuekehitys on vaarassa hidastua, jos alhaiseksi koetun riskin ehkäisemisestäei haluta maksaa.

A microarray-based system for the simultaneous analysis of single nucleotide polymorphisms in human genes involved in the metabolism of anti-malarial drugs

Background: In order to provide a cost-effective tool to analyse pharmacogenetic markers in malaria treatment, DNA microarray technology was compared with sequencing of polymerase chain reaction (PCR) fragments to detect single nucleotide polymorphisms (SNPs) in a larger number of samples. Methods: The microarray was developed to affordably generate SNP data of genes encoding the human cytochrome P450 enzyme family (CYP) and N-acetyltransferase-2 (NAT2) involved in antimalarial drug metabolisms and with known polymorphisms, i.e. CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, and NAT2. Results: For some SNPs, i.e. CYP2A6*2, CYP2B6*5, CYP2C8*3, CYP2C9*3/*5, CYP2C19*3, CYP2D6*4 and NAT2*6/*7/*14, agreement between both techniques ranged from substantial to almost perfect (kappa index between 0.61 and 1.00), whilst for other SNPs a large variability from slight to substantial agreement (kappa index between 0.39 and 1.00) was found, e. g. CYP2D6*17 (2850C>T), CYP3A4*1B and CYP3A5*3. Conclusion: The major limit of the microarray technology for this purpose was lack of robustness and with a large number of missing data or with incorrect specificity.

On the molecular basis of ion permeation in the epithelial Na+ channel.

The epithelial Na+ channel (ENaC) is highly selective for Na+ and Li+ over K+ and is blocked by the diuretic amiloride. ENaC is a heterotetramer made of two alpha, one beta, and one gamma homologous subunits, each subunit comprising two transmembrane segments. Amino acid residues involved in binding of the pore blocker amiloride are located in the pre-M2 segment of beta and gamma subunits, which precedes the second putative transmembrane alpha helix (M2). A residue in the alpha subunit (alphaS589) at the NH2 terminus of M2 is critical for the molecular sieving properties of ENaC. ENaC is more permeable to Li+ than Na+ ions. The concentration of half-maximal unitary conductance is 38 mM for Na+ and 118 mM for Li+, a kinetic property that can account for the differences in Li+ and Na+ permeability. We show here that mutation of amino acid residues at homologous positions in the pre-M2 segment of alpha, beta, and gamma subunits (alphaG587, betaG529, gammaS541) decreases the Li+/Na+ selectivity by changing the apparent channel affinity for Li+ and Na+. Fitting single-channel data of the Li+ permeation to a discrete-state model including three barriers and two binding sites revealed that these mutations increased the energy needed for the translocation of Li+ from an outer ion binding site through the selectivity filter. Mutation of betaG529 to Ser, Cys, or Asp made ENaC partially permeable to K+ and larger ions, similar to the previously reported alphaS589 mutations. We conclude that the residues alphaG587 to alphaS589 and homologous residues in the beta and gamma subunits form the selectivity filter, which tightly accommodates Na+ and Li+ ions and excludes larger ions like K+.

Prognostic value of sentinel node biopsy in 327 prospective melanoma patients from a single institution

Résumé Etude de la valeur pronostique de la biopsie du ganglion sentinelle dans une étude prospective monocentrique de 327 patients atteints de mélanome malin But II s'agit de confirmer la validité de la biopsie du ganglion sentinelle, d'en définir la morbidité, d'investiguer les facteurs prédictifs pour le statut du ganglion sentinelle ainsi que de déterminer les facteurs pronostiques pour la survie sans récidive et la survie spécifique liée à la maladie. Matériel et méthode D'octobre 1997 à décembre 2004, 327 patients consécutifs présentant un mélanome cutané primaire des membres, du tronc et de la tête, sans adénopathie clinique ni métastase à distance ont été inclus. La biopsie du ganglion sentinelle a été réalisée selon la triple technique (lymphoscintigraphie, colorant bleu vital et sonde de détection gamma). Les paramètres et la survie ont été évalués par différentes analyses de régression logistique multiple selon Cox et la survie évaluée selon Kaplan Meier. Résultats Vingt-trois pour cent des patients présentaient au moins un ganglion sentinelle métastatique, ce qui était associé de façon significative à l'épaisseur selon Breslow (p<0.001). Le taux de succès de la biopsie du ganglion sentinelle était de 99.1% et sa morbidité de 7.6%. Avec une durée médiane de suivi de 33 mois, la survie sans récidive à 5 ans était de 43% pour les patients avec un ganglion sentinelle positif et de 83.5% pour ceux avec un ganglion sentinelle négatif. La survie spécifique liée à la maladie à 5 ans était de 49% pour les patients avec un ganglion sentinelle positif et de 87.4% pour ceux avec un ganglion sentinelle négatif. Le taux de faux négatif de la biopsie du ganglion sentinelle était de 8.6%. L'analyse multivariée a démontré que la survie sans récidive était significativement péjorée par :l'épaisseur selon Breslow (RR=5.6, p<0.001), un ganglion sentinelle positif (RR=5.0, p<0.001), et le sexe masculin (RR=2.9, p=0.001). La survie spécifique liée à la maladie était significativement diminuée par : un ganglion sentinelle métastatique (RR=8.4, p<O.OOI), le sexe masculin (RR=6.1, p<0.001), l'épaisseur selon Breslow (RR=3.2, p=0.013), et la présence d'une ulcération (RR=2.6, p=0.015). Conclusion La biopsie du ganglion sentinelle est une procédure fiable avec une haute sensibilité (91.4%) et une faible morbidité (7.6%). L'épaisseur selon Breslow était le seul facteur prédictif significatif pour le statut du ganglion sentinelle. La survie sans récidive était péjorée selon un ordre décroissant par :l'épaisseur selon Breslow, un ganglion sentinelle métastatique, et le sexe masculin. De façon similaire la survie spécifique liée à la maladie était péjorée par : un ganglion sentinelle métastatique, le sexe masculin, l'épaisseur selon Breslow, et une ulcération. Ces données renforcent le statut du ganglion sentinelle en tant que puissant moyen pour évaluer le stade tumoral ainsi que le pronostic.

Single-trial multisensory memories affect later auditory and visual object discrimination.

Multisensory memory traces established via single-trial exposures can impact subsequent visual object recognition. This impact appears to depend on the meaningfulness of the initial multisensory pairing, implying that multisensory exposures establish distinct object representations that are accessible during later unisensory processing. Multisensory contexts may be particularly effective in influencing auditory discrimination, given the purportedly inferior recognition memory in this sensory modality. The possibility of this generalization and the equivalence of effects when memory discrimination was being performed in the visual vs. auditory modality were at the focus of this study. First, we demonstrate that visual object discrimination is affected by the context of prior multisensory encounters, replicating and extending previous findings by controlling for the probability of multisensory contexts during initial as well as repeated object presentations. Second, we provide the first evidence that single-trial multisensory memories impact subsequent auditory object discrimination. Auditory object discrimination was enhanced when initial presentations entailed semantically congruent multisensory pairs and was impaired after semantically incongruent multisensory encounters, compared to sounds that had been encountered only in a unisensory manner. Third, the impact of single-trial multisensory memories upon unisensory object discrimination was greater when the task was performed in the auditory vs. visual modality. Fourth, there was no evidence for correlation between effects of past multisensory experiences on visual and auditory processing, suggestive of largely independent object processing mechanisms between modalities. We discuss these findings in terms of the conceptual short term memory (CSTM) model and predictive coding. Our results suggest differential recruitment and modulation of conceptual memory networks according to the sensory task at hand.

A single epidermal stem cell strategy for safe ex vivo gene therapy.

There is a widespread agreement from patient and professional organisations alike that the safety of stem cell therapeutics is of paramount importance, particularly for ex vivo autologous gene therapy. Yet current technology makes it difficult to thoroughly evaluate the behaviour of genetically corrected stem cells before they are transplanted. To address this, we have developed a strategy that permits transplantation of a clonal population of genetically corrected autologous stem cells that meet stringent selection criteria and the principle of precaution. As a proof of concept, we have stably transduced epidermal stem cells (holoclones) obtained from a patient suffering from recessive dystrophic epidermolysis bullosa. Holoclones were infected with self-inactivating retroviruses bearing a COL7A1 cDNA and cloned before the progeny of individual stem cells were characterised using a number of criteria. Clonal analysis revealed a great deal of heterogeneity among transduced stem cells in their capacity to produce functional type VII collagen (COLVII). Selected transduced stem cells transplanted onto immunodeficient mice regenerated a non-blistering epidermis for months and produced a functional COLVII. Safety was assessed by determining the sites of proviral integration, rearrangements and hit genes and by whole-genome sequencing. The progeny of the selected stem cells also had a diploid karyotype, was not tumorigenic and did not disseminate after long-term transplantation onto immunodeficient mice. In conclusion, a clonal strategy is a powerful and efficient means of by-passing the heterogeneity of a transduced stem cell population. It guarantees a safe and homogenous medicinal product, fulfilling the principle of precaution and the requirements of regulatory affairs. Furthermore, a clonal strategy makes it possible to envision exciting gene-editing technologies like zinc finger nucleases, TALENs and homologous recombination for next-generation gene therapy.

A peroxisomal glutathione transferase of Saccharomyces cerevisiae is functionally related to sulfur amino acid metabolism

Saccharomyces cerevisiae cells contain three omega-class glutathione transferases with glutaredoxin activity (Gto1, Gto2, and Gto3), in addition to two glutathione transferases (Gtt1 and Gtt2) not classifiable into standard classes. Gto1 is located at the peroxisomes, where it is targeted through a PTS1-type sequence, whereas Gto2 and Gto3 are in the cytosol. Among the GTO genes, GTO2 shows the strongest induction of expression by agents such as diamide, 1-chloro-2,4-dinitrobenzene, tert-butyl hydroperoxide or cadmium, in a manner that is dependent on transcriptional factors Yap1 and/or Msn2/4. Diamide and 1-chloro-2,4-dinitrobenzene (causing depletion of reduced glutathione) also induce expression of GTO1 over basal levels. Phenotypic analyses with single and multiple mutants in the S. cerevisiae glutathione transferase genes show that, in the absence of Gto1 and the two Gtt proteins, cells display increased sensitivity to cadmium. A gto1-null mutant also shows growth defects on oleic acid-based medium, which is indicative of abnormal peroxisomal functions, and altered expression of genes related to sulfur amino acid metabolism. As a consequence, growth of the gto1 mutant is delayed in growth medium without lysine, serine, or threonine, and the mutant cells have low levels of reduced glutathione. The role of Gto1 at the S. cerevisiae peroxisomes could be related to the redox regulation of the Str3 cystathionine -lyase protein. This protein is also located at the peroxisomes in S. cerevisiae, where it is involved in transulfuration of cysteine into homocysteine, and requires a conserved cysteine residue for its biological activity.

Single acquisition electrical property mapping based on relative coil sensitivities: A proof-of-concept demonstration.

PURPOSE: All methods presented to date to map both conductivity and permittivity rely on multiple acquisitions to compute quantitatively the magnitude of radiofrequency transmit fields, B1+. In this work, we propose a method to compute both conductivity and permittivity based solely on relative receive coil sensitivities ( B1-) that can be obtained in one single measurement without the need to neither explicitly perform transmit/receive phase separation nor make assumptions regarding those phases. THEORY AND METHODS: To demonstrate the validity and the noise sensitivity of our method we used electromagnetic finite differences simulations of a 16-channel transceiver array. To experimentally validate our methodology at 7 Tesla, multi compartment phantom data was acquired using a standard 32-channel receive coil system and two-dimensional (2D) and 3D gradient echo acquisition. The reconstructed electric properties were correlated to those measured using dielectric probes. RESULTS: The method was demonstrated both in simulations and in phantom data with correlations to both the modeled and bench measurements being close to identity. The noise properties were modeled and understood. CONCLUSION: The proposed methodology allows to quantitatively determine the electrical properties of a sample using any MR contrast, with the only constraint being the need to have 4 or more receive coils and high SNR. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

1.48 and 1.84 µm thulium emissions in monoclinic KGd(WO4)2 single crystals

By exciting at 788 nm, we have characterized the near infrared emissions of trivalent thulium ions in monoclinic KGd(WO4)2 single crystals at 1.48 and 1.84 mm as a function of dopant concentration from 0.1% to 10% and temperature from 10 K to room temperature. We used the reciprocity method to calculate the maximum emission cross-section of 3.0310220 cm2 at 1.838 mm for the polarization parallel to the Nm principal optical direction. These results agrees well with the experimental data. Experimental decay times of the 3H4!3F4 and 3F4!3H6 transitions have been measured as a function of thulium concentration.