Role of cellular caspases, nuclear factor-kappa B and interferon regulatory factors in Bluetongue virus infection and cell fate

BACKGROUND: Bluetongue virus (BTV) infection causes haemorrhagic disease in ruminants and induces cell death. The pathogenesis in animals and in cell culture has been linked to BTV-induced apoptosis. RESULTS: In this report, we investigated BTV-induced apoptosis in cell culture in depth and show that both extrinsic (caspase-8 activation) and intrinsic (caspase-9 activation) pathways play roles in BTV apoptosis. Further, by using chemical inhibitors and knock-out cell lines, we show that these pathways act independently of each other in BTV infected cells. In addition to activation of caspase-8, -9 and executioner caspase-3, we also identified that BTV infection causes the activation of caspase-7, which results in the cleavage of poly (ADP-ribose) polymerase (PARP). BTV-induced cell death appears to be due to apoptosis rather than necrosis, as the HMBG-1 was not translocated from the nucleus. We also examined if NF-κB response is related to BTV-induced apoptosis as in reovirus. Our data suggests that NF-κB response is not linked to the induction of apoptosis. It is controlled by the degradation of only IκBα but not IκBβ, resulting in a rapid transient response during BTV infection. This was supported using an NF-κB dependent luciferase reporter gene assay, which demonstrated early response, that appeared to be suppressed by the late stage of BTV replication. Furthermore, virus titres were higher in the presence of NF-κB inhibitor (SN50), indicating that NF-κB has a role in initiating an antiviral environment. In addition, we show that BTV infection induces the translocation of interferon regulatory factors (IRF-3 and IRF-7) into the nucleus. The induction of IRF responses, when measured by IRF dependent luciferase reporter gene assay, revealed that the IRF responses, like NF-κB response, were also at early stage of infection and mirrored the timing of NF-κB induction. CONCLUSION: BTV triggers a wide range of caspase activities resulting in cell apoptosis. Although both NF-κB and IRF responses are induced by BTV infection, they are not sustained

Multidimensionality of Entrepreneurial Firm-level Processes: Do the Dimensions Covary?

Covariance (or not) among the first-order dimensions of firm-level entrepreneurial processes underpins a fundamental and non-trivial difference between the entrepreneurial orientation and entrepreneurial posture constructs. Utilizing a typology developed for multi-dimensional constructs, we operationalized each construct according to its specific conceptualization (relationships among the dimensions) and compared and contrasted each construct in an identical nomological network. Although we found support for both theories, the entrepreneurial orientation construct was more robust in explaining additional variance in growth. Additionally, our findings suggest that the means through which the first-order dimensions are operationalized—latent vs. summates— significantly affect the analysis

The effectiveness of Stepping Stones Triple P parenting support in parents of children with borderline to mild intellectual disability and psychosocial problems: a randomized controlled trial

Background: Children with borderline to mild intellectual disability (BMID) have been shown to be at increased risk for psychosocial problems. The presence of these psychosocial problems leads to parenting stress. Stepping Stones Triple P (SSTP) is a parenting support program to support parents with children with BMID and psychosocial problems. The aim of this study was to evaluate the effectiveness of SSTP compared to Care as Usual (CAU) in reducing psychosocial problems in children with BMID. Method: We conducted a randomized controlled trial in the Northern provinces of the Netherlands. Parents of children aged 5 to 12 with borderline (IQ 70 to 85) or mild (IQ 70 to 50) ID and psychosocial problems were invited. Psychosocial problems were identified using the Strengths and Difficulties Questionnaire (SDQ) parent report (>= 14). Measurements were assessed before the intervention (T0), immediately after the intervention (T1) and after a follow-up of six months (T2). SSTP takes 8 to 10 individual sessions of 40-90 minutes, provided over 10 to 12 weeks. CAU concerned any service, except SSTP. Primary outcomes were the child's psychosocial problems (SDQ parent and teacher forms and the Eyberg Child Behavior Inventory, ECBI). Secondary outcomes were parenting stress (Parenting Stress Index, PSI) and parenting skills (Alabama Parenting Questionnaire, APQ). Results: In total 209 parents of children aged 5 to 12 with BMID were allocated blindly to either SSTP (n = 111) or CAU (n = 98). In the intention to treat analyses, SSTP achieved no significantly better effect than CAU for the SDQ parent report, the ECBI and the APQ on the short- and long-term. In the short term, SSTP was significantly more effective than CAU for the SDQ teacher report (B = -2.25, 95% CI -3.79 to -0.71) and the PSI (B = -7.06, 95% CI -12.11 to -2.01). For both SDQ teacher report and PSI, there was no statistically significant effect in the long term. Dropout from SSTP was considerable (49%), with the effects being solely found in the adherent SSTP subgroup. Conclusions: SSTP had some short- term advantages over CAU, but not in the longer term

Multi-domain cognitive impairments at school age in very preterm-born children compared to term-born peers

Background Preterm infants are at risk for functional impairments in motor, cognitive, and behavioral development that may persist into childhood. The aim of this study was to determine the co-occurrence of cognitive impairments in multiple cognitive domains at school age in very preterm born children compared to term-born children. Methods Comparative study including 60 very preterm-born children (gestational age = 2), versus 3% of the controls (odds ratio, OR 4.65, 95%-confidence interval, CI 1.33-16.35). For multiple suspect-abnormal cognitive outcomes, rates were 55% versus 25% (OR 3.02, 95%-CI 1.49-6.12). We found no pattern of co-occurrence of cognitive impairments among preterm children that deviated from term-born controls. However, low performance IQ was more frequently accompanied by additional cognitive impairments in preterms than in controls (OR 5.43, 95%-CI 1.75-16.81). Conclusions A majority of preterm children showed co-occurrence of impairments in multiple cognitive domains, but with no specific pattern of impairments. The occurrence of multi-domain cognitive impairments is higher in preterms but this seems to reflect a general increase, not one with a pattern specific for preterm-born children

Validation of a Dutch version of the Tinnitus Functional Index in a tertiary referral tinnitus clinic

Introduction: Tinnitus is a condition with a subjective nature that requires self-report questionnaires for its assessment. Aspects such as quality of life, sleep or intrusiveness have been addressed by multiple tinnitus questionnaires, but the high responsiveness to treatment effects of the Tinnitus Functional Index (TFI) makes this questionnaire part of the standard practice in tinnitus screening. To date, the TFI has been translated to more than 20 languages and used in more than 22 countries. In this study, the TFI was translated to Dutch and validated through a clinical population in the Netherlands. Methods: After a back-translation procedure, the Dutch TFI was filled-out by 377 patients in the tinnitus outpatient clinic at the Ear, Nose and Throat (ENT) department of the University Medical Center Groningen, in the Netherlands. Reliability and construct validity of the questionnaire were assessed by correlations with one other tinnitus questionnaire (Tinnitus Handicap Inventory, THI) and with three psychological functioning questionnaires (Rand-36, Cantril's ladder and the Hospital Anxiety and Depression Scale (HADS)). The eight-factor structure of the Dutch TFI was tested by means of exploratory factor analysis using three different models (ICM-CFA, ESEM and ESEM-CFA). Results: The Dutch TFI showed a high internal consistency (α = 0.95), and construct validity was proven by moderate-to high-convergent correlations with the THI (r = 0.47–0.79) and by moderate convergent (r = 0.55–0.67) and good-to moderate-divergent (r = 0.12–0.47) correlations with the psychological functioning questionnaires. The eight-factor structure of the TFI was confirmed for the Dutch version by the three models. Conclusion: The Dutch version of the TFI is a reliable instrument for screening tinnitus impact in a clinical population, and its psychometric properties are comparable to the original TFI and other validated tinnitus questionnaires

Seasonal patterns in mindfulness in people with seasonal affective disorder (SAD)

Background: Mindfulness-based cognitive therapy (MBCT) is a well-known, effective treatment in the prevention of relapse in Major Depression Disorder (MDD). However, a recent study in people with Seasonal Affective Disorder (SAD) showed that MBCT given in spring was ineffective in preventing a next depressive episode. To test the hypothesis that people with SAD may experience sufficient levels of mindfulness in spring and therefore less benefit from MBCT, this study examines variations in levels of mindfulness over seasons. Methods: This longitudinal prospective study followed 77 people with SAD over a two-year period. Participants filled out a self-report questionnaire, Five Facet Mindfulness Questionnaire (FFMQ) on a quarterly basis. Results: Levels of mindfulness differed throughout the seasons, with overall results suggesting lower levels of mindfulness in winter. Limitations: The results are limited by the small sample size and varying levels of mindfulness over the two years of the study period. Conclusion: Findings suggest a seasonal component in levels of mindfulness exists, implying that people with SAD are less mindful during the winter compared to other seasons. Future research is needed to examine to what extent the motivation of people with SAD to participate in MBCT and benefit from it is higher in the winter

Questionnaire for usability evaluation of orthopaedic shoes: construction and reliability in patients with degenerative disorders of the foot

Objective: To develop a self-report questionnaire for patients with degenerative disorders of the foot to evaluate the usability of their orthopaedic shoes, and to assess the reproducibility and responsiveness of the instrument. Design: Development of the Questionnaire for Usability Evaluation of orthopaedic shoes was based on a literature search, structured expert interviews and a ranking procedure. A cross-sectional study was carried out to determine the reproducibility and internal consistency of the questionnaire. Setting and subjects: The study population comprised 15 patients with degenerative disorders of the foot, who had worn their orthopaedic shoes for at least 3 years and 15 patients with degenerative disorders of the foot, who had never worn orthopaedic shoes, but would receive them within 1 month. Results: Within the questionnaire 4 effectiveness items (pain, instability, callus, wounds), 1 efficiency item (putting on and taking off shoes) and 7 satisfaction items (pinch, slip, weight of shoes, cold feet, perspiration, maintenance, cosmetic appearance) were developed. All items in the questionnaire met the test-retest criteria. The smallest real difference ranged from 0.23 to 3.82 cm on a Visual Analogue Scale (10 cm). Cronbach's alpha's for the domains of pain and instability ranged from 0.70 to 0.92. Conclusion: The Questionnaire for Usability Evaluation should provide a good rationale to assess the usability of orthopaedic shoes and can be considered reliable