The Spread of Bluetongue Virus Serotype 8 in Great Britain and Its Control by Vaccination

Background

Bluetongue (BT) is a viral disease of ruminants transmitted by Culicoides biting midges and has the ability to spread rapidly over large distances. In the summer of 2006, BTV serotype 8 (BTV-8) emerged for the first time in northern Europe, resulting in over 2000 infected farms by the end of the year. The virus subsequently overwintered and has since spread across much of Europe, causing tens of thousands of livestock deaths. In August 2007, BTV-8 reached Great Britain (GB), threatening the large and valuable livestock industry. A voluntary vaccination scheme was launched in GB in May 2008 and, in contrast with elsewhere in Europe, there were no reported cases in GB during 2008.

Methodology/Principal Findings

Here, we use carefully parameterised mathematical models to investigate the spread of BTV in GB and its control by vaccination. In the absence of vaccination, the model predicted severe outbreaks of BTV, particularly for warmer temperatures. Vaccination was predicted to reduce the severity of epidemics, with the greatest reduction achieved for high levels (95%) of vaccine uptake. However, even at this level of uptake the model predicted some spread of BTV. The sensitivity of the predictions to vaccination parameters (time to full protection in cattle, vaccine efficacy), the shape of the transmission kernel and temperature dependence in the transmission of BTV between farms was assessed.

Conclusions/Significance

A combination of lower temperatures and high levels of vaccine uptake (>80%) in the previously-affected areas are likely to be the major contributing factors in the control achieved in England in 2008. However, low levels of vaccination against BTV-8 or the introduction of other serotypes could result in further, potentially severe outbreaks in future.     

A Spatial Simulation Model for the Dispersal of the Bluetongue Vector Culicoides brevitarsis in Australia

Background

The spread of Bluetongue virus (BTV) among ruminants is caused by movement of infected host animals or by movement of infected Culicoides midges, the vector of BTV. Biologically plausible models of Culicoides dispersal are necessary for predicting the spread of BTV and are important for planning control and eradication strategies.

Methods

A spatially-explicit simulation model which captures the two underlying population mechanisms, population dynamics and movement, was developed using extensive data from a trapping program for C. brevitarsis on the east coast of Australia. A realistic midge flight sub-model was developed and the annual incursion and population establishment of C. brevitarsis was simulated. Data from the literature was used to parameterise the model.

Results

The model was shown to reproduce the spread of C. brevitarsis southwards along the east Australian coastline in spring, from an endemic population to the north. Such incursions were shown to be reliant on wind-dispersal; Culicoides midge active flight on its own was not capable of achieving known rates of southern spread, nor was re-emergence of southern populations due to overwintering larvae. Data from midge trapping programmes were used to qualitatively validate the resulting simulation model.

Conclusions

The model described in this paper is intended to form the vector component of an extended model that will also include BTV transmission. A model of midge movement and population dynamics has been developed in sufficient detail such that the extended model may be used to evaluate the timing and extent of BTV outbreaks. This extended model could then be used as a platform for addressing the effectiveness of spatially targeted vaccination strategies or animal movement bans as BTV spread mitigation measures, or the impact of climate change on the risk and extent of outbreaks. These questions involving incursive Culicoides spread cannot be simply addressed with non-spatial models.     

Implicating Culicoides Biting Midges as Vectors of Schmallenberg Virus Using Semi-Quantitative RT-PCR

Background

The recent unprecedented emergence of arboviruses transmitted by Culicoides biting midges in northern Europe has necessitated the development of techniques to differentiate competent vector species. At present these techniques are entirely reliant upon interpretation of semi-quantitative RT-PCR (sqPCR) data in the form of C_q values used to infer the presence of viral RNA in samples.

Methodology/Principal Findings

This study investigates the advantages and limitations of sqPCR in this role by comparing infection and dissemination rates of Schmallenberg virus (SBV) in two colony lines of Culicoides. Through the use of these behaviorally malleable lines we provide tools for demarcating arbovirus infection and dissemination rates in Culicoides which to date have prevented clear implication of primary vector species in northern Europe. The study demonstrates biological transmission of SBV in an arthropod vector, supporting the conclusions from field-caught Culicoides and provides a general framework for future assessment of vector competence of Culicoides for arboviruses using sqPCR.

Conclusions/Significance

When adopting novel diagnostic technologies, correctly implicating vectors of arboviral pathogens requires a coherent laboratory framework to fully understand the implications of results produced in the field. This study illustrates these difficulties and provides a full examination of sqPCR in this role for the Culicoides-arbovirus system.     

Measurement of the Infection and Dissemination of Bluetongue Virus in Culicoides Biting Midges Using a Semi-Quantitative RT-PCR Assay and Isolation of Infectious Virus

Background

Culicoides biting midges (Diptera: Ceratopogonidae) are the biological vectors of globally significant arboviruses of livestock including bluetongue virus (BTV), African horse sickness virus (AHSV) and the recently emerging Schmallenberg virus (SBV). From 2006–2009 outbreaks of BTV in northern Europe inflicted major disruption and economic losses to farmers and several attempts were made to implicate Palaearctic Culicoides species as vectors. Results from these studies were difficult to interpret as they used semi-quantitative RT-PCR (sqPCR) assays as the major diagnostic tool, a technique that had not been validated for use in this role. In this study we validate the use of these assays by carrying out time-series detection of BTV RNA in two colony species of Culicoides and compare the results with the more traditional isolation of infectious BTV on cell culture.

Methodology/Principal Findings

A BTV serotype 1 strain mixed with horse blood was fed to several hundred individuals of Culicoides sonorensis (Wirth & Jones) and C. nubeculosus (Mg.) using a membrane-based assay and replete individuals were then incubated at 25°C. At daily intervals 25 Culicoides of each species were removed from incubation, homogenised and BTV quantified in each individual using sqPCR (C_q values) and virus isolation on a KC-C. sonorensis embryonic cell line, followed by antigen enzyme-linked immunosorbent assay (ELISA). In addition, comparisons were also drawn between the results obtained with whole C. sonorensis and with individually dissected individuals to determine the level of BTV dissemination.

Conclusions/Significance

C_q values generated from time-series infection experiments in both C. sonorensis and C. nubeculosus confirmed previous studies that relied upon the isolation and detection of infectious BTV. Implications on the testing of field-collected Culicoides as potential virus vectors by PCR assays and the use of such assays as front-line tools for use in diagnostic laboratories in this role are discussed.     

Entomopathogenic fungus as a biological control for an important vector of livestock disease: the Culicoides biting midge

Background

The recent outbreak of bluetongue virus in northern Europe has led to an urgent need to identify control measures for the Culicoides (Diptera: Ceratopogonidae) biting midges that transmit it. Following successful use of the entomopathogenic fungus Metarhizium anisopliae against larval stages of biting midge Culicoides nubeculosus Meigen, we investigated the efficacy of this strain and other fungi (Beauveria bassiana, Isaria fumosorosea and Lecanicillium longisporum) as biocontrol agents against adult C. nubeculosus in laboratory and greenhouse studies.

Methodology/Findings

Exposure of midges to ‘dry’ conidia of all fungal isolates caused significant reductions in survival compared to untreated controls. Metarhizium anisopliae strain V275 was the most virulent, causing a significantly decrease in midge survival compared to all other fungal strains tested. The LT₅₀ value for strain V275 was 1.42 days compared to 2.21–3.22 days for the other isolates. The virulence of this strain was then further evaluated by exposing C. nubeculosus to varying doses (10⁸–10¹¹ conidia m⁻²) using different substrates (horse manure, damp peat, leaf litter) as a resting site. All exposed adults were found to be infected with the strain V275 four days after exposure. A further study exposed C. nubeculosus adults to ‘dry’ conidia and ‘wet’ conidia (conidia suspended in 0.03% aq. Tween 80) of strain V275 applied to damp peat and leaf litter in cages within a greenhouse. ‘Dry’ conidia were more effective than ‘wet’ conidia, causing 100% mortality after 5 days.

Conclusion/Significance

This is the first study to demonstrate that entomopathogenic fungi are potential biocontrol agents against adult Culicoides, through the application of ‘dry’ conidia on surfaces (e.g., manure, leaf litter, livestock) where the midges tend to rest. Subsequent conidial transmission between males and females may cause an increased level of fungi-induced mortality in midges thus reducing the incidence of disease.     

Financial evaluation of different vaccination strategies for controlling the bluetongue virus serotype 8 epidemic in The Netherlands in 2008

Background

Bluetongue (BT) is a vector-borne disease of ruminants caused by bluetongue virus that is transmitted by biting midges (Culicoides spp.). In 2006, the introduction of BTV serotype 8 (BTV-8) caused a severe epidemic in Western and Central Europe. The principal effective veterinary measure in response to BT was believed to be vaccination accompanied by other measures such as movement restrictions and surveillance. As the number of vaccine doses available at the start of the vaccination campaign was rather uncertain, the Dutch Ministry of Agriculture, Nature and Food Quality and the Dutch agricultural industry wanted to evaluate several different vaccination strategies. This study aimed to rank eight vaccination strategies based on their efficiency (i.e. net costs in relation to prevented losses or benefits) for controlling the bluetongue virus serotype 8 epidemic in 2008.

Methodology/Principal Findings

An economic model was developed that included the Dutch professional cattle, sheep and goat sectors together with the hobby farms. Strategies were evaluated based on the least cost - highest benefit frontier, the benefit-cost ratio and the total net returns. Strategy F, where all adult sheep at professional farms in the Netherlands would be vaccinated was very efficient at lowest costs, whereas strategy D, where additional to all adult sheep at professional farms also all adult cattle in the four Northern provinces would be vaccinated, was also very efficient but at a little higher costs. Strategy C, where all adult sheep and cattle at professional farms in the whole of the Netherlands would be vaccinated was also efficient but again at higher costs.

Conclusions/Significance

This study demonstrates that a financial analysis differentiates between vaccination strategies and indicates important decision rules based on efficiency.     

A Modeling Framework to Describe the Transmission of Bluetongue Virus within and between Farms in Great Britain

Background

Recently much attention has been given to developing national-scale micro-simulation models for livestock diseases that can be used to predict spread and assess the impact of control measures. The focus of these models has been on directly transmitted infections with little attention given to vector-borne diseases such as bluetongue, a viral disease of ruminants transmitted by Culicoides biting midges. Yet BT has emerged over the past decade as one of the most important diseases of livestock.

Methodology/Principal Findings

We developed a stochastic, spatially-explicit, farm-level model to describe the spread of bluetongue virus (BTV) within and between farms. Transmission between farms was modeled by a generic kernel, which includes both animal and vector movements. Once a farm acquired infection, the within-farm dynamics were simulated based on the number of cattle and sheep kept on the farm and on local temperatures. Parameter estimates were derived from the published literature and using data from the outbreak of bluetongue in northern Europe in 2006. The model was validated using data on the spread of BTV in Great Britain during 2007. The sensitivity of model predictions to the shape of the transmission kernel was assessed.

Conclusions/Significance

The model is able to replicate the dynamics of BTV in Great Britain. Although uncertainty remains over the precise shape of the transmission kernel and certain aspects of the vector, the modeling approach we develop constitutes an ideal framework in which to incorporate these aspects as more and better data become available. Moreover, the model provides a tool with which to examine scenarios for the spread and control of BTV in Great Britain.     

Pervasive growth reduction in Norway spruce forests following wind disturbance

Background

In recent decades the frequency and severity of natural disturbances by e.g., strong winds and insect outbreaks has increased considerably in many forest ecosystems around the world. Future climate change is expected to further intensify disturbance regimes, which makes addressing disturbances in ecosystem management a top priority. As a prerequisite a broader understanding of disturbance impacts and ecosystem responses is needed. With regard to the effects of strong winds – the most detrimental disturbance agent in Europe – monitoring and management has focused on structural damage, i.e., tree mortality from uprooting and stem breakage. Effects on the functioning of trees surviving the storm (e.g., their productivity and allocation) have been rarely accounted for to date.

Methodology/Principal Findings

Here we show that growth reduction was significant and pervasive in a 6.79·million hectare forest landscape in southern Sweden following the storm Gudrun (January 2005). Wind-related growth reduction in Norway spruce (Picea abies (L.) Karst.) forests surviving the storm exceeded 10% in the worst hit regions, and was closely related to maximum gust wind speed (R² = 0.849) and structural wind damage (R² = 0.782). At the landscape scale, wind-related growth reduction amounted to 3.0 million m³ in the three years following Gudrun. It thus exceeds secondary damage from bark beetles after Gudrun as well as the long-term average storm damage from uprooting and stem breakage in Sweden.

Conclusions/Significance

We conclude that the impact of strong winds on forest ecosystems is not limited to the immediately visible area of structural damage, and call for a broader consideration of disturbance effects on ecosystem structure and functioning in the context of forest management and climate change mitigation.     

Using Wind Tunnels to Predict Bird Mortality in Wind Farms: The Case of Griffon Vultures

Background

Wind farms have shown a spectacular growth during the last 15 years. Avian mortality through collision with moving rotor blades is well-known as one of the main adverse impacts of wind farms. In Spain, the griffon vulture incurs the highest mortality rates in wind farms.

Methodology/Principal Findings

As far as we know, this study is the first attempt to predict flight trajectories of birds in order to foresee potentially dangerous areas for wind farm development. We analyse topography and wind flows in relation to flight paths of griffon vultures, using a scaled model of the wind farm area in an aerodynamic wind tunnel, and test the difference between the observed flight paths of griffon vultures and the predominant wind flows. Different wind currents for each wind direction in the aerodynamic model were observed. Simulations of wind flows in a wind tunnel were compared with observed flight paths of griffon vultures. No statistical differences were detected between the observed flight trajectories of griffon vultures and the wind passages observed in our wind tunnel model. A significant correlation was found between dead vultures predicted proportion of vultures crossing those cells according to the aerodynamic model.

Conclusions

Griffon vulture flight routes matched the predominant wind flows in the area (i.e. they followed the routes where less flight effort was needed). We suggest using these kinds of simulations to predict flight paths over complex terrains can inform the location of wind turbines and thereby reduce soaring bird mortality.     

Characterization of protection afforded by a bivalent virus-like particle vaccine against bluetongue virus serotypes 1 and 4 in sheep

Background

Bluetongue virus (BTV) is an economically important, arthropod borne, emerging pathogen in Europe, causing disease mainly in sheep and cattle. Routine vaccination for bluetongue would require the ability to distinguish between vaccinated and infected individuals (DIVA). Current vaccines are effective but are not DIVA. Virus-like particles (VLPs) are highly immunogenic structural mimics of virus particles, that only contain a subset of the proteins present in a natural infection. VLPs therefore offer the potential for the development of DIVA compatible bluetongue vaccines.

Methodology/Principal Findings

Merino sheep were vaccinated with either monovalent BTV-1 VLPs or a bivalent mixture of BTV-1 VLPs and BTV-4 VLPs, and challenged with virulent BTV-1 or BTV-4. Animals were monitored for clinical signs, antibody responses, and viral RNA. 19/20 animals vaccinated with BTV-1 VLPs either alone or in combination with BTV-4 VLPs developed neutralizing antibodies to BTV-1, and group specific antibodies to BTV VP7. The one animal that showed no detectable neutralizing antibodies, or group specific antibodies, had detectable viral RNA following challenge but did not display any clinical signs on challenge with virulent BTV-1. In contrast, all control animals'' demonstrated classical clinical signs for bluetongue on challenge with the same virus. Six animals were vaccinated with bivalent vaccine and challenged with virulent BTV-4, two of these animals had detectable viral levels of viral RNA, and one of these showed clinical signs consistent with BTV infection and died.

Conclusions

There is good evidence that BTV-1 VLPs delivered as monovalent or bivalent immunogen protect from bluetongue disease on challenge with virulent BTV-1. However, it is possible that there is some interference in protective response for BTV-4 in the bivalent BTV-1 and BTV-4 VLP vaccine. This raises the question of whether all combinations of bivalent BTV vaccines are possible, or if immunodominance of particular serotypes could interfere with vaccine efficacy.     

Polymorphisms in DNA-Repair Genes in a Cohort of Prostate Cancer Patients from Different Areas in Spain: Heterogeneity between Populations as a Confounding Factor in Association Studies

Background

Differences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics.

Objective

To evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias.

Design, Setting, and Participants

A total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArray® NT Cycler.

Outcome Measurements and Statistical Analysis

Comparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer.

Results and Limitations

We observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics.

Conclusion

Differences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta-analysis with subjects from different countries are carried out.     

Spatial and Temporal Distribution of Culicoides Species in Mainland Portugal (2005–2010). Results of the Portuguese Entomological Surveillance Programme

Bluetongue virus (BTV) is transmitted by Culicoides biting midges and causes an infectious, non-contagious disease of ruminants. It has been rapidly emerging in southern Europe since 1998. In mainland Portugal, strains of BTV belonging to three serotypes have been detected: BTV-10 (1956-1960), BTV-4 (2004-2006 and 2013) and BTV-1 (2007-2012). This paper describes the design, implementation and results of the Entomological Surveillance Programme covering mainland Portugal, between 2005 and 2010, including 5,650 caches. Culicoides imicola Kieffer was mostly found in central and southern regions of Portugal, although it was sporadically detected in northern latitudes. Its peak activity occurred in the autumn and it was active during the winter months in limited areas of the country. Obsoletus group was present at the highest densities in the north although they were found throughout the country in substantial numbers. Culicoides activity occurred all year round but peaked in the spring. A generalized linear mixed model was developed for the analysis of the environmental factors associated with activity of the species of Culicoides suspected vectors of BTV in the country. For C. imicola Kieffer, the most important variables were month, diurnal temperature range (DTR), the number of frost days (FRS) and median monthly temperature (TMP). For the Obsoletus group, the most important factors were month, diurnal temperature range (DTR), and linear and quadratic terms for median monthly temperature (TMP). The results reported can improve our understanding of climatic factors in Culicoides activity influencing their distribution and seasonal pattern.     

Health Effects Related to Wind Turbine Noise Exposure: A Systematic Review

Background

Wind turbine noise exposure and suspected health-related effects thereof have attracted substantial attention. Various symptoms such as sleep-related problems, headache, tinnitus and vertigo have been described by subjects suspected of having been exposed to wind turbine noise.

Objective

This review was conducted systematically with the purpose of identifying any reported associations between wind turbine noise exposure and suspected health-related effects.

Data Sources

A search of the scientific literature concerning the health-related effects of wind turbine noise was conducted on PubMed, Web of Science, Google Scholar and various other Internet sources.

Study Eligibility Criteria

All studies investigating suspected health-related outcomes associated with wind turbine noise exposure were included.

Results

Wind turbines emit noise, including low-frequency noise, which decreases incrementally with increases in distance from the wind turbines. Likewise, evidence of a dose-response relationship between wind turbine noise linked to noise annoyance, sleep disturbance and possibly even psychological distress was present in the literature. Currently, there is no further existing statistically-significant evidence indicating any association between wind turbine noise exposure and tinnitus, hearing loss, vertigo or headache.

Limitations

Selection bias and information bias of differing magnitudes were found to be present in all current studies investigating wind turbine noise exposure and adverse health effects. Only articles published in English, German or Scandinavian languages were reviewed.

Conclusions

Exposure to wind turbines does seem to increase the risk of annoyance and self-reported sleep disturbance in a dose-response relationship. There appears, though, to be a tolerable level of around L_Aeq of 35 dB. Of the many other claimed health effects of wind turbine noise exposure reported in the literature, however, no conclusive evidence could be found. Future studies should focus on investigations aimed at objectively demonstrating whether or not measureable health-related outcomes can be proven to fluctuate depending on exposure to wind turbines.     

Evidence for Transmission of Bluetongue Virus Serotype 26 through Direct Contact

The aim of this study was to assess the mechanisms of transmission of bluetongue virus serotype 26 (BTV-26) in goats. A previous study, which investigated the pathogenicity and infection kinetics of BTV-26 in goats, unexpectedly revealed that one control goat may have been infected through a direct contact transmission route. To investigate the transmission mechanisms of BTV-26 in more detail an experimental infection study was carried out in which three goats were infected with BTV-26, three goats were kept uninfected, but were housed in direct contact with the infected goats, and an additional four goats were kept in indirect contact separated from infected goats by metal gates. This barrier allowed the goats to have occasional face-to-face contact in the same airspace, but feeding, watering, sampling and environmental cleaning was carried out separately. The three experimentally infected goats did not show clinical signs of BTV, however high levels of viral RNA were detected and virus was isolated from their blood. At 21 dpi viral RNA was detected in, and virus was isolated from the blood of the three direct contact goats, which also seroconverted. The four indirect barrier contact goats remained uninfected throughout the duration of the experiment. In order to assess replication in a laboratory model species of Culicoides biting midge, more than 300 Culicoides sonorensis were fed a BTV-26 spiked blood meal and incubated for 7 days. The dissemination of BTV-26 in individual C. sonorensis was inferred from the quantity of virus RNA and indicated that none of the insects processed at day 7 possessed transmissible infections. This study shows that BTV-26 is easily transmitted through direct contact transmission between goats, and the strain does not seem to replicate in C. sonorensis midges using standard incubation conditions.     

Temperature dependence of the extrinsic incubation period of orbiviruses in Culicoides biting midges

Background

The rate at which viruses replicate and disseminate in competent arthropod vectors is limited by the temperature of their environment, and this can be an important determinant of geographical and seasonal limits to their transmission by arthropods in temperate regions.

Methodology/Principal Findings

Here, we present a novel statistical methodology for estimating the relationship between temperature and the extrinsic incubation period (EIP) and apply it to both published and novel data on virus replication for three internationally important orbiviruses (African horse sickness virus (AHSV), bluetongue virus (BTV) and epizootic haemorrhagic disease virus (EHDV)) in their Culicoides vectors. Our analyses show that there can be differences in vector competence for different orbiviruses in the same vector species and for the same orbivirus in different vector species. Both the rate of virus replication (approximately 0.017-0.021 per degree-day) and the minimum temperature required for replication (11-13°C), however, were generally consistent for different orbiviruses and across different Culicoides vector species. The estimates obtained in the present study suggest that previous publications have underestimated the replication rate and threshold temperature because the statistical methods they used included an implicit assumption that all negative vectors were infected.

Conclusions/Significance

Robust estimates of the temperature dependence of arbovirus replication are essential for building accurate models of transmission and for informing policy decisions about seasonal relaxations to movement restrictions. The methodology developed in this study provides the required robustness and is superior to methods used previously. Importantly, the methods are generic and can readily be applied to other arbovirus-vector systems, as long as the assumptions described in the text are valid.     

Centennial olive trees as a reservoir of genetic diversity

Background and Aims

Genetic characterization and phylogenetic analysis of the oldest trees could be a powerful tool both for germplasm collection and for understanding the earliest origins of clonally propagated fruit crops. The olive tree (Olea europaea L.) is a suitable model to study the origin of cultivars due to its long lifespan, resulting in the existence of both centennial and millennial trees across the Mediterranean Basin.

Methods

The genetic identity and diversity as well as the phylogenetic relationships among the oldest wild and cultivated olives of southern Spain were evaluated by analysing simple sequence repeat markers. Samples from both the canopy and the roots of each tree were analysed to distinguish which trees were self-rooted and which were grafted. The ancient olives were also put into chronological order to infer the antiquity of traditional olive cultivars.

Key Results

Only 9·6 % out of 104 a priori cultivated ancient genotypes matched current olive cultivars. The percentage of unidentified genotypes was higher among the oldest olives, which could be because they belong to ancient unknown cultivars or because of possible intra-cultivar variability. Comparing the observed patterns of genetic variation made it possible to distinguish which trees were grafted onto putative wild olives.

Conclusions

This study of ancient olives has been fruitful both for germplasm collection and for enlarging our knowledge about olive domestication. The findings suggest that grafting pre-existing wild olives with olive cultivars was linked to the beginnings of olive growing. Additionally, the low number of genotypes identified in current cultivars points out that the ancient olives from southern Spain constitute a priceless reservoir of genetic diversity.     

Immunomodulatory Effects of Escherichia coli ATCC 25922 on Allergic Airway Inflammation in a Mouse Model

Background

Hygiene hypothesis demonstrates that the lack of microbial exposure would promote the development of allergic airway disease (AAD). Therefore, the gut microbiota, including Escherichia coli (E. coli), would probably offer a potential strategy for AAD.

Objective

To investigate whether E. coli infection is able to suppress the induction of AAD and to elucidate the underlying mechanisms.

Methods

Nonpathogenic E. coli ATCC 25922 was infected by gavage before AAD phase in three patterns: 10⁸ or 10⁶ CFU in neonates or 10⁸ CFU in adults. Then mice were sensitized and challenged with ovalbumin (OVA) to induce allergic inflammation in both the upper and lower airways. Hallmarks of AAD, in terms of eosinophil infiltration and goblet cell metaplasia in subepithelial mucosa, Th2 skewing of the immune response, and levels of T regulate cells (Tregs), were examined by histological analysis, ELISA, and flow cytometry, respectively.

Results

E. coli, especially neonatally infected with an optimal dose, attenuated allergic responses, including a decrease in nasal rubbing and sneezing, a reduction in eosinophil inflammation and goblet cell metaplasia in subepithelial mucosa, decreased serum levels of OVA-specific IgE, and reduced Th2 (IL-4) cytokines. In contrast, this effect came with an increase of Th1 (IFN-r and IL-2) cytokines, and an enhancement of IL-10-secreting Tregs in paratracheal lymph nodes (PTLN).

Conclusion

E. coli suppresses allergic responses in mice, probably via a shift from Th1 to Th2 and/or induction of Tregs. Moreover, this infection is age- and dose-dependent, which may open up novel possibilities for new therapeutic interventions.     

Early PTSD Symptom Trajectories: Persistence,Recovery, and Response to Treatment: Results from the Jerusalem Trauma Outreach and Prevention Study (J-TOPS)

Context

Uncovering heterogeneities in the progression of early PTSD symptoms can improve our understanding of the disorder''s pathogenesis and prophylaxis.

Objectives

To describe discrete symptom trajectories and examine their relevance for preventive interventions.

Design

Latent Growth Mixture Modeling (LGMM) of data from a randomized controlled study of early treatment. LGMM identifies latent longitudinal trajectories by exploring discrete mixture distributions underlying observable data.

Setting

Hadassah Hospital unselectively receives trauma survivors from Jerusalem and vicinity.

Participants

Adult survivors of potentially traumatic events consecutively admitted to the hospital''s emergency department (ED) were assessed ten days and one-, five-, nine- and fifteen months after ED admission. Participants with data at ten days and at least two additional assessments (n = 957) were included; 125 received cognitive behavioral therapy (CBT) between one and nine months.

Approach

We used LGMM to identify latent parameters of symptom progression and tested the effect of CBT on these parameters. CBT consisted of 12 weekly sessions of either cognitive therapy (n = 41) or prolonged exposure (PE, n = 49), starting 29.8±5.7 days after ED admission, or delayed PE (n = 35) starting at 151.8±42.4 days. CBT effectively reduced PTSD symptoms in the entire sample.

Main Outcome Measure

Latent trajectories of PTSD symptoms; effects of CBT on these trajectories.

Results

Three trajectories were identified: Rapid Remitting (rapid decrease in symptoms from 1- to 5-months; 56% of the sample), Slow Remitting (progressive decrease in symptoms over 15 months; 27%) and Non-Remitting (persistently elevated symptoms; 17%). CBT accelerated the recovery of the Slow Remitting class but did not affect the other classes.

Conclusions

The early course of PTSD symptoms is characterized by distinct and diverging response patterns that are centrally relevant to understanding the disorder and preventing its occurrence. Studies of the pathogenesis of PTSD may benefit from using clustered symptom trajectories as their dependent variables.     

Impact of IL28B-related single nucleotide polymorphisms on liver histopathology in chronic hepatitis C genotype 2 and 3

Background and Aims

Recently, several genome-wide association studies have revealed that single nucleotide polymorphisms (SNPs) in proximity to IL28B predict spontaneous clearance of HCV infection as well as outcome following peginterferon and ribavirin therapy among HCV genotype 1 infected patients. The present study aimed to evaluate the impact of IL28B SNP variability on liver histology in the context of a phase III treatment trial (NORDynamIC) for treatment-naïve patients with chronic HCV genotype 2 or 3 infection, where pretreatment liver biopsies were mandatory.

Methods

Three hundred and thirty-nine Caucasian patients had samples available for IL28B genotyping (rs12979860) of whom 314 had pretreatment liver biopsies that were evaluated using the Ishak protocol, allowing for detailed grading and staging of liver histopathology.

Results

IL28B CC_rs12979860 genotype in HCV genotype 3 infected patients was associated with higher ALT levels (p<0.0001), higher AST to platelet ratio index (APRI; p = 0.001), and higher baseline viral load (p<0.0001) as compared to patients with the CT or TT genotypes. Additionally the CC_rs12979860 genotype entailed more pronounced portal inflammation (p = 0.02) and steatosis (p = 0.03). None of these associations were noted among HCV genotype 2 infected patients.

Conclusion

This study shows that the CC_rs12979860 SNP is associated with more pronounced liver histopathology in patients chronically infected with HCV genotype 3, which may be secondary to higher viral load. The finding that IL28B variability did not impact on liver pathology or viral load among genotype 2 infected patients implies that IL28B may differentially regulate the course of genotype 2 and 3 infection.