Cell-Mediated Immunity to AAV Vectors, Evolving Concepts and Potential Solutions

International audienceAdeno-associated virus (AAV) vectors are one of the most efficient in vivo gene delivery platforms. Over the past decade, clinical trials of AAV vector-mediated gene transfer led to some of the most exciting results in the field of gene therapy and, recently, to the market approval of an AAV-based drug in Europe. With clinical development, however, it became obvious that the host immune system represents an important obstacle to successful gene transfer with AAV vectors. In this review article, we will discuss the issue of cytotoxic T cell responses directed against the AAV capsid encountered on human studies. While over the past several years the field has acquired a tremendous amount of information on the interactions of AAV vectors with the immune system, a lot of questions are still unanswered. Novel concepts are emerging, such as the relationship between the total capsid dose and the T cell-mediated clearance of transduced cells, the potential role of innate immunity in vector immunogenicity highlighted in preclinical studies, and the cross talk between regulatory and effector T cells in the determination of the outcome of gene transfer. There is still a lot to learn about immune responses in AAV gene transfer, for example, it is not well understood what are the determinants of the kinetics of activation of T cells in response to vector administration, why not all subjects develop detrimental T cell responses following gene transfer, and whether the intervention strategies currently in use to block T cell-mediated clearance of transduced cells will be safe and effective for all gene therapy indications. Results from novel preclinical models and clinical studies will help to address these points and to reach the important goal of developing safe and effective gene therapy protocols to treat human diseases

Noise Effects on Health in the Context of Air Pollution Exposure

For public health policy and planning it is important to understand the relative contribution of environmental noise on health compared to other environmental stressors. Air pollution is the primary environmental stressor in relation to cardiovascular morbidity and mortality. This paper reports a narrative review of studies in which the associations of both environmental noise and air pollution with health have been examined. Studies of hypertension, myocardial infarction, stroke, mortality and cognitive outcomes were included. Results suggest independent effects of environmental noise from road traffic, aircraft and, with fewer studies, railway noise on cardiovascular outcomes after adjustment for air pollution. Comparative burden of disease studies demonstrate that air pollution is the primary environmental cause of disability adjusted life years lost (DALYs). Environmental noise is ranked second in terms of DALYs in Europe and the DALYs attributed to noise were more than those attributed to lead, ozone and dioxins. In conclusion, in planning and health impact assessment environmental noise should be considered an independent contributor to health risk which has a separate and substantial role in ill-health separate to that of air pollution

Investigating transport of dust particles in plasmas

An algorithm has been developped, which makes it possible to automatically extract trajectories of a large number of particles from fast imaging data, allowing a statistical analysis of particles trajectories under various plasma conditions, a better understanding of their influence on plasma properties, and a better characterization of the plasma itself. In this contribution, we focus on results obtained in a radiofrequency parallel plate reactor, where a large amount of micron-sized carbon dust is produced in situ. The use of the rescaled range analysis (R/S analysis) applied to dust particles displacements allows decomposing dust dynamic on different time scales. It is shown that dust displacement is dominated by collisions on short time scales whereas long term behaviour is strongly influenced by large scale plasma fluctuations.Comment: This version contains 8 pages and 5 figures. This work has been presented in the 1st Int. Conf. on Plasma Diagnostics, O8, April 12-16 2010, Pont-\`a-Mousson, France (2010). It has been submitted to Contribution to Plasma Physic

Protocol for the Reconstructing Consciousness and Cognition (ReCCognition) Study

Important scientific and clinical questions persist about general anesthesia despite the ubiquitous clinical use of anesthetic drugs in humans since their discovery. For example, it is not known how the brain reconstitutes consciousness and cognition after the profound functional perturbation of the anesthetized state, nor has a specific pattern of functional recovery been characterized. To date, there has been a lack of detailed investigation into rates of recovery and the potential orderly return of attention, sensorimotor function, memory, reasoning and logic, abstract thinking, and processing speed. Moreover, whether such neurobehavioral functions display an invariant sequence of return across individuals is similarly unknown. To address these questions, we designed a study of healthy volunteers undergoing general anesthesia with electroencephalography and serial testing of cognitive functions (NCT01911195). The aims of this study are to characterize the temporal patterns of neurobehavioral recovery over the first several hours following termination of a deep inhaled isoflurane general anesthetic and to identify common patterns of cognitive function recovery. Additionally, we will conduct spectral analysis and reconstruct functional networks from electroencephalographic data to identify any neural correlates (e.g., connectivity patterns, graph-theoretical variables) of cognitive recovery after the perturbation of general anesthesia. To accomplish these objectives, we will enroll a total of 60 consenting adults aged 20–40 across the three participating sites. Half of the study subjects will receive general anesthesia slowly titrated to loss of consciousness (LOC) with an intravenous infusion of propofol and thereafter be maintained for 3 h with 1.3 age adjusted minimum alveolar concentration of isoflurane, while the other half of subjects serves as awake controls to gauge effects of repeated neurobehavioral testing, spontaneous fatigue and endogenous rest-activity patterns

Nocturnal air, road, and rail traffic noise and daytime cognitive performance and annoyance

Various studies indicate that at the same noise level and during the daytime, annoyance increases in the order of rail, road, and aircraft noise. The present study investigates if the same ranking can be found for annoyance to nocturnal exposure and next day cognitive performance. Annoyance ratings and performance change during combined noise exposure were also tested. In the laboratory 72 participants were exposed to air, road, or rail traffic noise and all combinations. The number of noise events and LAS,eq were kept constant. Each morning noise annoyance questionnaires and performance tasks were administered. Aircraft noise annoyance ranked first followed by railway and road noise. A possible explanation is the longer duration of aircraft noise events used in this study compared to road and railway noise events. In contrast to road and rail traffic, aircraft noise annoyance was higher after nights with combined exposure. Pooled noise exposure data showed small but significant impairments in reaction times (6 ms) compared to nights without noise. The noise sources did not have a differential impact on performance. Combined exposure to multiple traffic noise sources did not induce stronger impairments than a single noise source. This was reflected also in low workload ratings

Inflight Pharmacokinetic and Pharmacodynamic Responses to Medications Commonly Used in Spaceflight

Researchers do not know if medications act the same in the spaceflight environment as they do on Earth. Aspects of the spaceflight environment (low gravity, radiation exposure, closed environment, stress) have been shown to alter human physiology. Some of these physiological changes could be expected to alter either pharmacokinetics (PK, how the body absorbs, distributes, metabolizes and excretes administered medications) or pharmacodynamics (PD, receptors or signaling systems that are the targets of medication action). Anecdotal data has suggested that, at least for certain medications or indications, inflight medication efficacy is poor. In order to prepare for exploration missions where speedy evacuation to Earth may not be a possibility, the likelihood of unexpected medication action must be determined

Auralization of Amplitude Modulated Helicopter Flyover Noise

Rotorcraft noise is an active field of study as the sound produced by these vehicles is often found to be annoying. A means to auralize rotorcraft flyover noise is sought to help understand the factors leading to annoyance. Previous work by the authors auralized a complete flyover event in which the source noise synthesis traversed a range of emission angles. The source noise definition process for the synthesis used helicopter flyover recordings. Although this process yielded both periodic and aperiodic (modulation) components at a set of discrete emission angles, only the periodic components were used in the previous work to synthesize the sound of the flyover event. In the current work, aperiodic amplitude modulation is incorporated into the source noise synthesis to improve its fidelity toward assessing rotorcraft noise annoyance. The method is demonstrated using ground recordings from a flight test of the AS350 helicopter for the source noise definition

Determining physiological reaction probabilities to noise events during sleep

Some of the activations that occur during sleep, e.g. awakening reactions, can be considered adverse effects of noise events (e.g., airplane overflights or train passings) during the night. The occurrence of such reactions is an important indicator of the sleep disturbing potential of the particular noise stimulus and it is often desired to exactly quantify that potential in terms of a probability. Awakenings are considered the strongest form of reaction to noise stimuli during sleep and are one of the most often adopted criteria in night time noise protection concepts. However, the correct determination of noise induced awakening probability has given rise to debate in the scientific community in recent years. Because during every night's sleep, spontaneous awakenings can occur at any time, it remains unknown in principle, whether a particular awakening observed during the presence of a noise stimulus was induced by that stimulus or emerged spontaneously. Nevertheless, correctly determining the awakening probability in question is key when it comes to forecasting noise effects during the night. This article introduces two definitions of reaction probability, discusses their advantages and disadvantages, and develops a model of the influence of the time window duration in which reactions of sleepers are screened on the calculated reaction probabilit

Sleep During Pregnancy: The nuMoM2b Pregnancy and Sleep Duration and Continuity Study

Study Objectives: To characterize sleep duration, timing and continuity measures in pregnancy and their association with key demographic variables. Methods: Multisite prospective cohort study. Women enrolled in the nuMoM2b study (nulliparous women with a singleton gestation) were recruited at the second study visit (16-21 weeks of gestation) to participate in the Sleep Duration and Continuity substudy. Women <18 years of age or with pregestational diabetes or chronic hypertension were excluded from participation. Women wore a wrist activity monitor and completed a sleep log for 7 consecutive days. Time in bed, sleep duration, fragmentation index, sleep efficiency, wake after sleep onset, and sleep midpoint were averaged across valid primary sleep periods for each participant. Results: Valid data were available from 782 women with mean age of 27.3 (5.5) years. Median sleep duration was 7.4 hours. Approximately 27.9% of women had a sleep duration of 9 hours. In multivariable models including age, race/ethnicity, body mass index, insurance status, and recent smoking history, sleep duration was significantly associated with race/ethnicity and insurance status, while time in bed was only associated with insurance status. Sleep continuity measures and sleep midpoint were significantly associated with all covariates in the model, with the exception of age for fragmentation index and smoking for wake after sleep onset. Conclusions: Our results demonstrate the relationship between sleep and important demographic characteristics during pregnancy