Morphological and functional correlates of vestibular synaptic deafferentation and repair in a mouse model of acute-onset vertigo.

Damage to cochlear primary afferent synapses has been shown to be a key factor in various auditory pathologies. Similarly, the selective lesioning of primary vestibular synapses might be an underlying cause of peripheral vestibulopathies that cause vertigo and dizziness, for which the pathophysiology is currently unknown. To thoroughly address this possibility, we selectively damaged the synaptic contacts between hair cells and primary vestibular neurons in mice through the transtympanic administration of a glutamate receptor agonist. Using a combination of histological and functional approaches, we demonstrated four key findings: (1) selective synaptic deafferentation is sufficient to generate acute vestibular syndrome with characteristics similar to those reported in patients; (2) the reduction of the vestibulo-ocular reflex and posturo-locomotor deficits mainly depends on spared synapses; (3) damaged primary vestibular synapses can be repaired over the days and weeks following deafferentation; and (4) the synaptic repair process occurs through the re-expression and re-pairing of synaptic proteins such as CtBP2 and SHANK-1. Primary synapse repair might contribute to re-establishing the initial sensory network. Deciphering the molecular mechanism that supports synaptic repair could offer a therapeutic opportunity to rescue full vestibular input and restore gait and balance in patients.

Immunogenicity of AS03-adjuvanted and non-adjuvanted trivalent inactivated influenza vaccines in elderly adults: A Phase 3, randomized trial and post-hoc correlate of protection analysis.

In this study we describe the immunogenicity results from a subset of older people (N = 5187) who participated in a Phase 3 randomized, observer-blinded trial of AS03-TIV versus TIV (Fluarix™) (ClinicalTrials.gov, NCT00753272). Participants received one dose of AS03-TIV or TIV in each study year and antibody titers against the vaccine strains were assessed using hemagglutination-inhibition (HI) assay at 21 d and 180 d post-vaccination in each vaccine group in the 2008/09 (Year 1) and 2009/10 (Year 2) influenza seasons. Manufacturing consistency of 3 lots of AS03-TIV for HI antibody responses in Year 1 was a co-primary objective. In a post-hoc analysis, a statistical regression model included 4830 subjects in whom immunogenicity and laboratory-confirmed attack rate data were available; the analysis was performed to assess HI antibody titers against A/H3N2 as a correlate of protection for laboratory-confirmed A/H3N2 influenza. AS03-TIV and TIV elicited strong HI antibody responses against each vaccine strain 21 d post-vaccination in both years. The manufacturing consistency of 3 lots of AS03-TIV was demonstrated. In both years and each vaccine group, HI antibody responses were lower for A/H1N1 than the other vaccine strains. Day 180 seroconversion rates (proportion with ≥4-fold increase in titer compared with pre-vaccination titer) in Year 1 in the AS03-TIV and TIV groups, respectively, were 87.7% and 74.1% for A/H3N2, 69.7% and 59.6% for influenza B, and 58.3% and 47.4% for A/H1N1. The post-hoc statistical model based on A/H3N2 attack rates and HI antibody titers estimated that a 4-fold increase in post-vaccination titers against A/H3N2 was associated with a 2-fold decrease in the odds of A/H3N2 infection.

Hemagglutination Inhibition Antibody Titers as a Correlate of Protection Against Seasonal A/H3N2 Influenza Disease.

Background. To investigate the relationship between hemagglutinin-inhibition (HI) antibody levels to the risk of influenza disease, we conducted a correlate of protection analysis using pooled data from previously published randomized trials. Methods. Data on the occurrence of laboratory-confirmed influenza and HI levels pre- and postvaccination were analyzed from 4 datasets: 3 datasets included subjects aged <65 years who received inactivated trivalent influenza vaccine (TIV) or placebo, and 1 dataset included subjects aged ≥65 years who received AS03-adjuvanted TIV (AS03-TIV) or TIV. A logistic model was used to evaluate the relationship between the postvaccination titer of A/H3N2 HI antibodies and occurrence of A/H3N2 disease. We then built a receiver-operating characteristic curve to identify a potential cutoff titer between protection and no protection. Results. The baseline odds ratio of A/H3N2 disease was higher for subjects aged ≥65 years than <65 years and higher in seasons of strong epidemic intensity than moderate or low intensity. Including age and epidemic intensity as covariates, a 4-fold increase in titer was associated with a 2-fold decrease in the risk of A/H3N2 disease. Conclusions. The modeling exercise confirmed a relationship between A/H3N2 disease and HI responses, but it did not allow an evaluation of the predictive power of the HI response.

Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.

Sustained-release fampridine (fampridine-SR) improves gait velocity and self-perceived capacities in people with multiple sclerosis (MS). However, little is known about the treatment's effect on temporospatial gait parameters, walking endurance, general fatigue, hand function and quality of life (QoL). We therefore sought to evaluate these parameters in a real-world setting: 120 consecutive, eligible patients with MS were evaluated at baseline (D0) and after two weeks (D14) of fampridine-SR. Lastly, D14 responders were again evaluated after three months (M3). Response to treatment was defined as a 15% improvement in at least one of the following tests: the Timed 25-Foot-Walk (T25FW), the 2-min walk test (2MWT) and the Multiple Sclerosis Walking Scale (MSWS-12). Eighty-three patients (74%) were found to be responders. The response rate was lower when assessed as a 20% improvement in the T25FW (50.9%), and this difference was particularly marked for fast-walking subjects (i.e. T25FW <8 s at baseline). Responders displayed mean improvements (at D14 and M3, respectively) of 34.5 and 35.5% in the T25FW, 39 and 36.7% in the 2MWT and 19 and 11.6% in the MSWS-12. The increase in gait velocity was due to both a higher cadence and a greater step length. Responders showed also significant, lasting reductions in fatigue (visual analogue scale and the Fatigue Severity Scale; p < 10(-4) at D14 and <0.01 at M3) and significant, lasting improvements in hand function (9 Hole Peg Test; p < 0.05) and QoL (SF-12; p < 0.01). In conclusion, several MS-induced symptoms other than gait velocity may be improved by fampridine-SR, even if this remains to be more specifically evaluated in future studies.

Influenza vaccine efficacy trials: a simulation approach to understand failures from the past.

The success of a seasonal influenza vaccine efficacy trial depends not only upon the design but also upon the annual epidemic characteristics. In this context, simulation methods are an essential tool in evaluating the performances of study designs under various circumstances. However, traditional methods for simulating time-to-event data are not suitable for the simulation of influenza vaccine efficacy trials because of the seasonality and heterogeneity of influenza epidemics. Instead, we propose a mathematical model parameterized with historical surveillance data, heterogeneous frailty among the subjects, survey-based heterogeneous number of daily contact, and a mixed vaccine protection mechanism. We illustrate our methodology by generating multiple-trial data similar to a large phase III trial that failed to show additional relative vaccine efficacy of an experimental adjuvanted vaccine compared with the reference vaccine. We show that small departures from the designing assumptions, such as a smaller range of strain protection for the experimental vaccine or the chosen endpoint, could lead to smaller probabilities of success in showing significant relative vaccine efficacy.

Assessing vaccine efficacy in influenza clinical trials: challenges and difficulties.

The efficacy assessment of an influenza vaccine often requires conducting large and expensive clinical trials. Specificities of influenza increase the complexity of the study designs, of the subsequent statistical analysis and of the interpretation of the results. They include low attack rates, seasonality, multiplicity and frequent mutations of flu viruses as well as heterogeneity of virus circulation, varying annual vaccine composition and so on. The authors discuss how those factors may impact the design, the conduct and the analysis of an efficacy trial and explain why it may fail whatever the true vaccine efficacy. The authors then argue that extending the length to several consecutive seasons is an alternative to the frequently used 1-year design and propose refinements of the statistical models.

Anticipating root displacements: unlocking new prospects.

OBJECTIVE: The aim of this study was to visualize and quantify root displacements in the bone base of a patient before orthodontic treatment and obtain an optimal set-up that would include information on both coronal and root movements. MATERIAL AND METHOD: Data from a patient's scan records, the initial plaster model and scanned set-up are migrated into the Amira® software for advanced mesh and surface analysis. Using this software, each tooth of the initial 3D-reconstruction scan is isolated then superimposed over that of the initial model. The set-up is then positioned onto the initial model at second molar level and dragged onto the initial 3D reconstruction. Lastly, the roots are repositioned on the crowns on the set-up. RESULTS: This study enabled the visualization and quantification of dental displacements (crowns and roots) from initial to expected final position in a three-dimensional space reconstruction. DISCUSSION-CONCLUSION: This technique, carried out routinely thanks to the advent of cone beam tomography, can help optimize orthodontic treatments, notably by anticipating root proximity issues during set-up preparation.

Exploration of the retinal nerve fiber layer thickness by measurement of the linear dichroism.

An electro-optic device mounted on a slit lamp to assess the degree of polarization of a light beam that has double passed through the retina about the optic-nerve head in the living human eye is described. The asymmetric structure of the retinal nerve's fiber layer possesses a linear-form dichroism and will partially polarize an unpolarized light beam that is scattered at the fundus of the eye and has double passed the ocular media (cornea, lens, retina). This partial polarization is a function of the retinal nerve's fiber layer thickness, and its measurement may be used for exploring glaucoma and other retinal neuropathies. Experimental conditions allow us to neglect corneal dichroism. The first clinical measurements show a different degree of polarization between normal and glaucomatous eyes and a good correlation with the results obtained by optical coherence tomography.

Structure-activity relationships of dengue antiviral polycyclic quinones.

The virucidal and antiviral photoactivities of three compounds, hypericin, tetrabromohypericin and gymnochrome B, were evaluated against dengue viruses. All the three products were active, and both the virucidal and antiviral activities were enhanced by light. Gymnochrome B was more potent than hypericin and tetrabromohypericin. The presence of the side chains on the hypericin core of gymnochromes appears to be beneficial for both virucidal and antiviral activities. This enhanced activity is likely to be linked to a complementary mechanism independent of photoactivation.

Linear dichroism of the cornea.

The dichroic properties of in vitro sheep corneas were studied with a spectrophotometer in transmission mode for several angles of incidence of light beams. Several models of corneal anisotropy have been presented in the literature. The results presented here allow us to believe that the cornea behaves as a dichroic biaxial crystal. Furthermore, this dichroism is weak when the angle of incidence on the corneal surface stays small. The mathematical model that describes these optical properties of the cornea uses Mueller matrices.