In vitro allergy tests compared to intradermal testing in horses with recurrent airway obstruction

Recurrent airway obstruction (RAO) is a common condition in stabled horses characterised by small airway inflammation, airway neutrophilia and obstruction following exposure of susceptible horses to mouldy hay and straw and is thus regarded as a hypersensitivity reaction to mould spores. However, the role of IgE-mediated reactions in RAO remains unclear. The aim of the study was to investigate with a serological IgE ELISA test (Allercept), an in vitro sulfidoleukotriene (sLT) release assay (CAST) and with intradermal testing (IDT) whether serum IgE and IgE-mediated reactions against various mould, mite and pollen extracts are associated with RAO. IDT reactions were evaluated at different times in order to detect IgE-mediated immediate type reactions (type I hypersensitivity reactions, 0.5-1 h), immune complex-mediated late type reactions (type III reactions, 4-10 h) and cell-mediated delayed type reactions (type IV hypersensitivity reactions 24-48 h). In the serological test, overall the control horses displayed more positive reactions than the RAO-affected horses but the difference was not significant. Comparison of the measured IgE levels showed that the RAO-affected horses had slightly higher IgE levels against Aspergillus fumigatus than controls (35 and 16 AU, respectively, p<0.05), but all values were below the cut off (150 AU) of the test. In the sLT release assay, seven positive reactions were observed in the RAO-affected horses and four in the controls but this difference was not significant. A significantly higher proportion of late type IDT reactions was observed in RAO-affected horses compared to controls (25 of 238 possible reactions versus 12 of 238 possible reactions, respectively, p<0.05). Interestingly, four RAO-affected but none of the control horses reacted with the recombinant mould allergen A. fumigatus 8 (rAsp f 8, p<0.05), but only late phase and delayed type reactions were observed. In all three tests the majority of the positive reactions was observed with the mite extracts (64%, 74% and 88% of all positive reactions, respectively) but none of the tests showed a significant difference between RAO-affected and control animals. Our findings do not support that IgE-mediated reactions are important in the pathogenesis of RAO. Further studies are needed to investigate whether sensitisation to mite allergens is of clinical relevance in the horse and to understand the role of immune reactions against rAsp f 8.

A whole-genome scan for recurrent airway obstruction in Warmblood sport horses indicates two positional candidate regions

Recurrent airway obstruction (RAO), or heaves, is a naturally occurring asthma-like disease that is related to sensitisation and exposure to mouldy hay and has a familial basis with a complex mode of inheritance. A genome-wide scanning approach using two half-sibling families was taken in order to locate the chromosome regions that contribute to the inherited component of this condition in these families. Initially, a panel of 250 microsatellite markers, which were chosen as a well-spaced, polymorphic selection covering the 31 equine autosomes, was used to genotype the two half-sibling families, which comprised in total 239 Warmblood horses. Subsequently, supplementary markers were added for a total of 315 genotyped markers. Each half-sibling family is focused around a severely RAO-affected stallion, and the phenotype of each individual was assessed for RAO and related signs, namely, breathing effort at rest, breathing effort at work, coughing, and nasal discharge, using an owner-based questionnaire. Analysis using a regression method for half-sibling family structures was performed using RAO and each of the composite clinical signs separately; two chromosome regions (on ECA13 and ECA15) showed a genome-wide significant association with RAO at P < 0.05. An additional 11 chromosome regions showed a more modest association. This is the first publication that describes the mapping of genetic loci involved in RAO. Several candidate genes are located in these regions, a number of which are interleukins. These are important signalling molecules that are intricately involved in the control of the immune response and are therefore good positional candidates.

Mixed inheritance of equine recurrent airway obstruction

BACKGROUND: Mode of inheritance of equine recurrent airway obstruction (RAO) is unknown. HYPOTHESIS: Major genes are responsible for RAO. ANIMALS: Direct offspring of 2 RAO-affected Warmblood stallions (n = 197; n = 163) and a representative sample of Swiss Warmbloods (n = 401). METHODS: One environmental and 4 genetic models (general, mixed inheritance, major gene, and polygene) were tested for Horse Owner Assessed Respiratory Signs Index (1-4, unaffected to severely affected) by segregation analyses of the 2 half-sib sire families, both combined and separately, using prevalences estimated in a representative sample. RESULTS: In all data sets the mixed inheritance model was most likely to explain the pattern of inheritance. In all 3 datasets the mixed inheritance model did not differ significantly from the general model (P= .62, P= 1.00, and P= .27) but was always better than the major gene model (P < .01) and the polygene model (P < .01). The frequency of the deleterious allele differed considerably between the 2 sire families (P= .23 and P= .06). In both sire families the displacement was large (t= 17.52 and t= 12.24) and the heritability extremely large (h(2)= 1). CONCLUSIONS AND CLINICAL RELEVANCE: Segregation analyses clearly reveal the presence of a major gene playing a role in RAO. In 1 family, the mode of inheritance was autosomal dominant, whereas in the other family it was autosomal recessive. Although the expression of RAO is influenced by exposure to hay, these findings suggest a strong, complex genetic background for RAO.

Use of EORTC Target Definition Guidelines for Dose-Intensified Salvage Radiation Therapy for Recurrent Prostate Cancer: Results of the Quality Assurance Program of the Randomized Trial SAKK 09/10

PURPOSE Different international target volume delineation guidelines exist and different treatment techniques are available for salvage radiation therapy (RT) for recurrent prostate cancer, but less is known regarding their respective applicability in clinical practice. METHODS AND MATERIALS A randomized phase III trial testing 64 Gy vs 70 Gy salvage RT was accompanied by an intense quality assurance program including a site-specific and study-specific questionnaire and a dummy run (DR). Target volume delineation was performed according to the European Organisation for the Research and Treatment of Cancer guidelines, and a DR-based treatment plan was established for 70 Gy. Major and minor protocol deviations were noted, interobserver agreement of delineated target contours was assessed, and dose-volume histogram (DVH) parameters of different treatment techniques were compared. RESULTS Thirty European centers participated, 43% of which were using 3-dimensional conformal RT (3D-CRT), with the remaining centers using intensity modulated RT (IMRT) or volumetric modulated arc technique (VMAT). The first submitted version of the DR contained major deviations in 21 of 30 (70%) centers, mostly caused by inappropriately defined or lack of prostate bed (PB). All but 5 centers completed the DR successfully with their second submitted version. The interobserver agreement of the PB was moderate and was improved by the DR review, as indicated by an increased κ value (0.59 vs 0.55), mean sensitivity (0.64 vs 0.58), volume of total agreement (3.9 vs 3.3 cm(3)), and decrease in the union volume (79.3 vs 84.2 cm(3)). Rectal and bladder wall DVH parameters of IMRT and VMAT vs 3D-CRT plans were not significantly different. CONCLUSIONS The interobserver agreement of PB delineation was moderate but was improved by the DR. Major deviations could be identified for the majority of centers. The DR has improved the acquaintance of the participating centers with the trial protocol.

Induction of lucid dreams: A systematic review of evidence

In lucid dreams the dreamer is aware of dreaming and often able to influence the ongoing dream content. Lucid dreaming is a learnable skill and a variety of techniques is suggested for lucid dreaming induction. This systematic review evaluated the evidence for the effectiveness of induction techniques. A comprehensive literature search was carried out in biomedical databases and specific resources. Thirty-five studies were included in the analysis (11 sleep laboratory and 24 field studies), of which 26 employed cognitive techniques, 11 external stimulation and one drug application. The methodological quality of the included studies was relatively low. None of the induction techniques were verified to induce lucid dreams reliably and consistently, although some of them look promising. On the basis of the reviewed studies, a taxonomy of lucid dream induction methods is presented. Several methodological issues are discussed and further directions for future studies are proposed.

Effects of task modality, length and complexity on time for activities in lucid dreams

Introduction: Nocturnal dreams can be considered as a kind of simulation of the real world on a higher cognitive level (Erlacher & Schredl, 2008). Within lucid dreams, the dreamer is aware of the dream state and thus able to control the ongoing dream content. Previous studies could demonstrate that it is possible to practice motor tasks during lucid dreams and doing so improved performance while awake (Erlacher & Schredl, 2010). Even though lucid dream practice might be a promising kind of cognitive rehearsal in sports, little is known about the characteristics of actions in lucid dreams. The purpose of the present study was to explore the relationship between time in dreams and wakefulness because in an earlier study (Erlacher & Schredl, 2004) we found that performing squads took lucid dreamers 44.5 % more time than in the waking state while for counting the same participants showed no differences between dreaming and wakefulness. To find out if the task modality, the task length or the task complexity require longer times in lucid dreams than in wakefulness three experiments were conducted. Methods: In the first experiment five proficient lucid dreamers spent two to three non-consecutive nights in the sleep laboratory with polysomnographic recording to control for REM sleep and determine eye signals. Participants counted from 1-10, 1-20 and 1-30 in wakefulness and in their lucid dreams. While dreaming they marked onset of lucidity as well as beginning and end of the counting task with a Left-Right-Left-Right eye movement and reported their dreams after being awakened. The same procedure was used for the second experiment with seven lucid dreamers except that they had to walk 10, 20 or 30 steps. In the third experiment nine participants performed an exercise involving gymnastics elements such as various jumps and a roll. To control for length of the task the gymnastic exercise in the waking state lasted about the same time as walking 10 steps. Results: As a general result we found – as in the study before – that performing a task in the lucid dream requires more time than in wakefulness. This tendency was found for all three tasks. However, there was no difference for the task modality (counting vs. motor task). Also the relative time for the different lengths of the tasks showed no difference. And finally, the more complex motor task (gymnastic routine) did not require more time in lucid dreams than the simple motor task. Discussion/Conclusion: The results showed that there is a robust effect of time in lucid dreams compared to wakefulness. The three experiments could not explain that those differences are caused by task modality, task length or task complexity. Therefore further possible candidates needs to be investigated e.g. experience in lucid dreaming or psychological variables. References: Erlacher, D. & Schredl, M. (2010). Practicing a motor task in a lucid dream enhances subsequent performance: A pilot study. The Sport Psychologist, 24(2), 157-167. Erlacher, D. & Schredl, M. (2008). Do REM (lucid) dreamed and executed actions share the same neural substrate? International Journal of Dream Research, 1(1), 7-13. Erlacher, D. & Schredl, M. (2004). Time required for motor activity in lucid dreams. Perceptual and Motor Skills, 99, 1239-1242.

Reconstructive Dreams: A Pragmatic Fantastic After Postmodernism

This dissertation focuses on the use of fantastic elements in the work of a young generation of writers which explore the possibilities of literary development after and beyond postmodernism. By overtly declaring the fictionality of their fantastic stories by means of frame narratives, texts like Jonathan Safran Foer’s Everything is Illuminated (2002), Michael Chabon’s The Amazing Adventures of Kavalier and Clay (2000), Mark Danielewski’s House of Leaves (2000), David Mitchell’s number9dream (2001) and Yann Martel’s Life of Pi (2001) reassess the communicative value of genre boundaries in an attempt to move beyond postmodern relativity and breakdown of communicability. This clear focus on pragmatic concerns marks a shift in the use of the fantastic which calls for a reconsideration of some of the general critical assumptions about the workings of the mode. Though the relation between reality and fiction remains a central issue, the main concern shifts away from such epistemological and ontological considerations, towards questions concerning the pragmatic function of literary fiction in general and different genres in particular. Instead of dwelling on the typically postmodern concerns about the fictionality of reality and the instability of meaning, the works under discussion emphasise the constructive role fiction plays in dealing with reality, the uses to which it can be put and the functions it fulfils in fashioning our being in the world. Drawing on Iser’s theory of the fictive, Irmtraud Huber therefore suggests a reconceptualisation of the fantastic mode, which newly foregrounds its underlying pragmatic structure. She bring this adapted understanding to bear in a close textual analysis of the above mentioned literary texts, with the aim to account for their use of the mode in their commitment to a larger literary endeavour of a new generation that engages with the inheritance of postmodernism and struggles to come into its own.

Late recurrent arrhythmias after ablation of atrial fibrillation: incidence, mechanisms, and treatment.

OBJECTIVES The aim of the study was to determine the incidence of atrial flutter and other arrhythmia recurrences (other than atrial fibrillation [AF]) during long-term follow-up after left atrial substrate modification by percutaneous radiofrequency (RF) ablation of AF. BACKGROUND RF ablation is an effective treatment for patients with AF. However, late recurrent arrhythmias may complicate the patient's course. METHODS One hundred fifty consecutive patients with paroxysmal or persistent AF were included in this prospective study. The incidence of arrhythmia recurrences after AF ablation was analyzed during long-term follow-up using repetitive 7-day ECG recording. RESULTS In 28 of 150 patients (18.7%), stable regular arrhythmias other than AF were detected during follow-up. Left atrial flutter observed in 10 patients (6.7%) was treated by recompletion of the ablation lines in all 10 patients. Left atrial flutter was associated with recurrence of AF in all 10 patients. Nine of 10 patients (90%) were free from atrial flutter and 6 of 10 patients were free from AF after the second intervention. Typical right atrial flutter occurred in 10 patients (6.7%) and was treated successfully by percutaneous RF ablation without recurrence in all patients. Additionally, atrial flutter was documented during follow-up in 7 patients (4.7%); however, invasive electrophysiologic evaluation was not performed due to various reasons. CONCLUSIONS Left atrial flutter is a relevant complication after RF catheter ablation of AF and was always associated with AF recurrence in our study population. Prevention of left atrial flutter can be achieved by induction of ablation lines as continuous and transmural as possible. However, left atrial flutter that does occur late after ablation is amenable to interventional treatment with good prospects of success.

Correlation between subjective evaluation of symptoms and objective findings in early recurrent head and neck squamous cell carcinoma

IMPORTANCE This study addresses the value of patients' reported symptoms as markers of tumor recurrence after definitive therapy for head and neck squamous cell carcinoma. OBJECTIVE To evaluate the correlation between patients' symptoms and objective findings in the diagnosis of local and/or regional recurrences of head and neck squamous cell carcinomas in the first 2 years of follow-up. DESIGN Retrospective single-institution study of a prospectively collected database. SETTING Regional hospital. PARTICIPANTS We reviewed the clinical records of patients treated for oral cavity, oropharyngeal, laryngeal, and hypopharyngeal carcinomas between January 1, 2008, and December 31, 2009, with a minimum follow-up of 2 years. MAIN OUTCOMES AND MEASURES Correlation between symptoms and oncologic status (recurrence vs remission) in the posttreatment period. RESULTS Of the 101 patients included, 30 had recurrences. Pain, odynophagia, and dysphonia were independently correlated with recurrence (odds ratios, 16.07, 11.20, and 5.90, respectively; P < .001). New-onset symptoms had the best correlation with recurrences. Correlation was better between 6 to 12 and 18 to 21 months after therapy and in patients initially treated unimodally (P < .05). Primary stage and tumor site had no effect. CONCLUSIONS AND RELEVANCE The correlation between symptoms and oncologic status is low during substantial periods within the first 2 years of follow-up. New-onset symptoms, especially pain, odynophagia, or dysphonia, better correlate with tumor recurrence, especially in patients treated unimodally.

Effect of hay dust extract and cyathostomin antigen stimulation on cytokine expression by PBMC in horses with recurrent airway obstruction

Equine recurrent airway obstruction (RAO) is an inflammatory, obstructive airway disease induced by exposure of susceptible horses to inhaled organic dust particles. The immunological process underlying RAO is still unclear. Previous studies have shown that RAO is linked to the Interleukin-4 receptor (IL-4R) gene in one Warmblood family (F1), but not in another (F2). It has also been shown that in F1, but not in F2, RAO is associated with resistance against parasites, suggesting that this association may have an immuno-genetic basis. Therefore, we hypothesized that the T helper (h)1/Th2/regulatory (Treg) cytokine profiles of RAO-associated antigen- and parasite-antigen-stimulated peripheral blood mononuclear cells (PBMC) differ between RAO-affected and healthy horses depending on their genetic background. In our study, PBMC from 17 RAO-affected and 14 healthy control horses of F1 and F2 were stimulated for 24h with antigens relevant to RAO [hay dust extract (HDE), Aspergillus fumigatus extract (AFE) and lipopolysaccharids (LPS)]; cyathostomin extract (CE) and recombinant cyathostomin antigen (RCA) or with concanavalin A (ConA). Total mRNA levels of IL-4, IL-4R, IL-13, interferon (INF)-γ and IL-10 were examined by qRT-PCR. Stimulation with either HDE or RCA resulted in significant differences in IL-4R mRNA levels between RAO-affected and control horses in F1, but not in F2. For IL-10 mRNA expression, a significant difference between RAO-affected and control horses in F1 but not in F2 was observed only following stimulation with HDE. In contrast to HDE, stimulation with CE resulted in a significant difference of IL-10 mRNA expression level between RAO-affected horses of F2 and healthy horses of F1. No significant differences were detected upon stimulation with any of the other challenge agents. These findings indicate that the immunological response, specifically IL-4R expression, in response to hay dust and cyathostomin antigens, differs between RAO-affected and healthy horses depending on their genetic background. This study shows that analysis of PBMC reveals systemic changes associated with RAO and helps to elucidate immunological pathways involved in this disease.

Risk of very early recurrent cerebrovascular events in symptomatic carotid artery stenosis

OBJECT The risk of recurrence of cerebrovascular events within the first 72 hours of admission in patients hospitalized with symptomatic carotid artery (CA) stenoses and the risks and benefits of emergency CA intervention within the first hours after the onset of symptoms are not well known. Therefore, the authors aimed to assess (1) the ipsilateral recurrence rate within 72 hours of admission, in the period from 72 hours to 7 days, and after 7 days in patients presenting with nondisabling stroke, transient ischemic attack (TIA), or amaurosis fugax (AF), and with an ipsilateral symptomatic CA stenosis of 50% or more, and (2) the risk of stroke in CA interventions within 48 hours of admission versus the risk in interventions performed after 48 hours. METHODS Ninety-four patients were included in this study. These patients were admitted to hospital within 48 hours of a nondisabling stroke, TIA, or AF resulting from a symptomatic CA stenosis of 50% or more. The patients underwent carotid endarterectomy (85 patients) or CA stenting (9 patients). At baseline, the cardiovascular risk factors of the patients, the degree of symptomatic CA stenosis, and the type of secondary preventive treatment were assessed. The in-hospital recurrence rate of stroke, TIA, or AF ipsilateral to the symptomatic CA stenosis was determined for the first 72 hours after admission, from 72 hours to 7 days, and after 7 days. Procedure-related cerebrovascular events were also recorded. RESULTS The median time from symptom onset to CA intervention was 5 days (interquartile range 3.00-9.25 days). Twenty-one patients (22.3%) underwent CA intervention within 48 hours after being admitted. Overall, 15 recurrent cerebrovascular events were observed in 12 patients (12.8%) in the period between admission and CA intervention: 3 strokes (2 strokes in progress and 1 stroke) (3.2%), 5 TIAs (5.3%), and 1 AF (1.1%) occurred within the first 72 hours (total 9.6%) of admission; 1 TIA (1.1%) occurred between 72 hours and 7 days, and 5 TIAs (5.3%) occurred after more than 7 days. The corresponding actuarial cerebrovascular recurrence rates were 11.4% (within 72 hours of admission), 2.4% (between 72 hours and 7 days), and 7.9% (after 7 days). Among baseline characteristics, no predictive factors for cerebrovascular recurrence were identified. Procedure-related cerebrovascular events occurred at a rate of 4.3% (3 strokes and 1 TIA), and procedures performed within the first 48 hours and procedures performed after 48 hours had a similar frequency of these events (4.5% vs. 4.1%, respectively; p = 0.896). CONCLUSIONS The in-hospital recurrence of cerebrovascular events was quite low, but all recurrent strokes occurred within 72 hours. The risk of stroke associated with a CA intervention performed within the first 48 hours was not increased compared with that for later interventions. This raises the question of the optimal timing of CA intervention in symptomatic CA stenosis. To answer this question, more data are needed, preferably from large randomized trials.

Building silent compartments at the nuclear periphery: a recurrent theme.

In eukaryotes, the genetic material is stored in the nucleus, which is enclosed in a double lipid bilayer, the nuclear envelope (NE). It protects the genome from physical stress and separates it from the rest of the cell. On top of this physical function, growing evidence shows that the nuclear periphery contributes to the 3D organization of the genome. In turn, tridimensional organization of chromatin in the nuclear space influences genome expression. Here we review recent findings on the function of this physical barrier in gene repression and latest models on how silent subnuclear compartments at the NE are built in yeast as well as in the nematode C. elegans and mammalian cells; trying to draw parallels between the three systems.

Loss of TRAIL-receptors is a recurrent feature in pancreatic cancer and determines the prognosis of patients with no nodal metastasis after surgery

INTRODUCTION Agonistic antibodies targeting TRAIL-receptors 1 and 2 (TRAIL-R1 and TRAIL-R2) are being developed as a novel therapeutic approach in cancer therapy including pancreatic cancer. However, the cellular distribution of these receptors in primary pancreatic cancer samples has not been sufficiently investigated and no study has yet addressed the issue of their prognostic significance in this tumor entity. AIMS AND METHODS Applying tissue microarray (TMA) analysis, we performed an immunohistochemical assessment of TRAIL-receptors in surgical samples from 84 consecutive patients affected by pancreatic adenocarcinoma and in 26 additional selected specimens from patients with no lymph nodes metastasis at the time of surgery. The prognostic significance of membrane staining and staining intensity for TRAIL-receptors was evaluated. RESULTS The fraction of pancreatic cancer samples with positive membrane staining for TRAIL-R1 and TRAIL-R2 was lower than that of cells from surrounding non-tumor tissues (TRAIL-R1: p<0.001, TRAIL-R2: p = 0.006). In addition, subgroup analyses showed that loss of membrane staining for TRAIL-R2 was associated with poorer prognosis in patients without nodal metastases (multivariate Cox regression analysis, Hazard Ratio: 0.44 [95% confidence interval: 0.22-0.87]; p = 0.019). In contrast, analysis of decoy receptors TRAIL-R3 and -R4 in tumor samples showed an exclusively cytoplasmatic staining pattern and no prognostic relevance. CONCLUSION This is a first report on the prognostic significance of TRAIL-receptors expression in pancreatic cancer showing that TRAIL-R2 might represent a prognostic marker for patients with early stage disease. In addition, our data suggest that loss of membrane-bound TRAIL-receptors could represent a molecular mechanism for therapeutic failure upon administration of TRAIL-receptors-targeting antibodies in pancreatic cancer. This hypothesis should be evaluated in future clinical trials.