Transglutaminase 2 limits the extravasation and the resultant myocardial fibrosis associated with factor XIII-A deficiency

Background and aims Transglutaminase (TG) 2 and Factor (F) XIII-A have both been implicated in cardiovascular protection and repair. This study was designed to differentiate between two competing hypotheses: that TG2 and FXIII-A mediate these functions in mice by fulfilling separate roles, or that they act redundantly in this respect. Methods Atherosclerosis was assessed in brachiocephalic artery plaques of fat-fed mixed strain apolipoprotein (Apo)e deficient mice that lacked either or both transglutaminases. Cardiac fibrosis was assessed both in the mixed strain mice and also in C57BL/6J Apoe expressing mice lacking either or both transglutaminases. Results No difference was found in the density of buried fibrous caps within brachiocephalic plaques from mice expressing or lacking these transglutaminases. Cardiac fibrosis developed in both Apoe/F13a1 double knockout and F13a1 single knockout mice, but not in Tgm2 knockout mice. However, concomitant Tgm2 knockout markedly increased fibrosis, as apparent in both Apoe/Tgm2/F13a1 knockout and Tgm2/F13a1 knockout mice. Amongst F13a1 knockout and Tgm2/F13a1 knockout mice, the extent of fibrosis correlated with hemosiderin deposition, suggesting that TG2 limits the extravasation of blood in the myocardium, which in turn reduces the pro-fibrotic stimulus. The resulting fibrosis was interstitial in nature and caused only minor changes in cardiac function. Conclusions These studies confirm that FXIII-A and TG2 fulfil different roles in the mouse myocardium. FXIII-A protects against vascular leakage while TG2 contributes to the stability or repair of the vasculature. The protective function of TG2 must be considered when designing clinical anti-fibrotic therapies based upon FXIII-A or TG2 inhibition

A Systematic Review of Mosquito Coils and Passive Emanators: Defining Recommendations for Spatial Repellency Testing Methodologies.

Mosquito coils, vaporizer mats and emanators confer protection against mosquito bites through the spatial action of emanated vapor or airborne pyrethroid particles. These products dominate the pest control market; therefore, it is vital to characterize mosquito responses elicited by the chemical actives and their potential for disease prevention. The aim of this review was to determine effects of mosquito coils and emanators on mosquito responses that reduce human-vector contact and to propose scientific consensus on terminologies and methodologies used for evaluation of product formats that could contain spatial chemical actives, including indoor residual spraying (IRS), long lasting insecticide treated nets (LLINs) and insecticide treated materials (ITMs). PubMed, (National Centre for Biotechnology Information (NCBI), U.S. National Library of Medicine, NIH), MEDLINE, LILAC, Cochrane library, IBECS and Armed Forces Pest Management Board Literature Retrieval System search engines were used to identify studies of pyrethroid based coils and emanators with key-words "Mosquito coils" "Mosquito emanators" and "Spatial repellents". It was concluded that there is need to improve statistical reporting of studies, and reach consensus in the methodologies and terminologies used through standardized testing guidelines. Despite differing evaluation methodologies, data showed that coils and emanators induce mortality, deterrence, repellency as well as reduce the ability of mosquitoes to feed on humans. Available data on efficacy outdoors, dose-response relationships and effective distance of coils and emanators is inadequate for developing a target product profile (TPP), which will be required for such chemicals before optimized implementation can occur for maximum benefits in disease control

A novel extracellular role for tissue transglutaminase in matrix-bound VEGF-mediated angiogenesis

The importance of tissue transglutaminase (TG2) in angiogenesis is unclear and contradictory. Here we show that inhibition of extracellular TG2 protein crosslinking or downregulation of TG2 expression leads to inhibition of angiogenesis in cell culture, the aorta ring assay and in vivo models. In a human umbilical vein endothelial cell (HUVEC) co-culture model, inhibition of extracellular TG2 activity can halt the progression of angiogenesis, even when introduced after tubule formation has commenced and after addition of excess vascular endothelial growth factor (VEGF). In both cases, this leads to a significant reduction in tubule branching. Knockdown of TG2 by short hairpin (shRNA) results in inhibition of HUVEC migration and tubule formation, which can be restored by add back of wt TG2, but not by the transamidation-defective but GTP-binding mutant W241A. TG2 inhibition results in inhibition of fibronectin deposition in HUVEC monocultures with a parallel reduction in matrix-bound VEGFA, leading to a reduction in phosphorylated VEGF receptor 2 (VEGFR2) at Tyr1214 and its downstream effectors Akt and ERK1/2, and importantly its association with b1 integrin. We propose a mechanism for the involvement of matrix-bound VEGFA in angiogenesis that is dependent on extracellular TG2-related activity

Clusters versus Affinity-Based Approaches in F. tularensis Whole Genome Search of CTL Epitopes

Deciphering the cellular immunome of a bacterial pathogen is challenging due to the enormous number of putative peptidic determinants. State-of-the-art prediction methods developed in recent years enable to significantly reduce the number of peptides to be screened, yet the number of remaining candidates for experimental evaluation is still in the range of ten-thousands, even for a limited coverage of MHC alleles. We have recently established a resource-efficient approach for down selection of candidates and enrichment of true positives, based on selection of predicted MHC binders located in high density “hotspots" of putative epitopes. This cluster-based approach was applied to an unbiased, whole genome search of Francisella tularensis CTL epitopes and was shown to yield a 17–25 fold higher level of responders as compared to randomly selected predicted epitopes tested in Kb/Db C57BL/6 mice. In the present study, we further evaluate the cluster-based approach (down to a lower density range) and compare this approach to the classical affinity-based approach by testing putative CTL epitopes with predicted IC50 values of <10 nM. We demonstrate that while the percent of responders achieved by both approaches is similar, the profile of responders is different, and the predicted binding affinity of most responders in the cluster-based approach is relatively low (geometric mean of 170 nM), rendering the two approaches complimentary. The cluster-based approach is further validated in BALB/c F. tularensis immunized mice belonging to another allelic restriction (Kd/Dd) group. To date, the cluster-based approach yielded over 200 novel F. tularensis peptides eliciting a cellular response, all were verified as MHC class I binders, thereby substantially increasing the F. tularensis dataset of known CTL epitopes. The generality and power of the high density cluster-based approach suggest that it can be a valuable tool for identification of novel CTLs in proteomes of other bacterial pathogens

Downregulation of MIP-1α/CCL3 with praziquantel treatment in Schistosoma haematobium and HIV-1 co-infected individuals in a rural community in Zimbabwe

The results of our study show that the MIP-1alpha/CCL3 levels were positively associated with S. haematobium egg counts at baseline but not with HIV-1 infection status. MIP-1alpha/CCL3 levels were significantly reduced at three months post treatment with praziquantel. We therefore conclude that MIP-1alpha/CCL3 is produced during infection with S haematobium. S. haematobium infection is associated with increased MIP-1alpha/CCL3 levels in an egg intensity-dependent manner and treatment of S. haematobium is associated with a reduction in MIP-1alpha/CCL3

Determining utility values in patients with anterior cruciate ligament tears using clinical scoring systems

BACKGROUND: Several instruments and clinical scoring systems have been established to evaluate patients with ligamentous knee injuries. A comparison of individual articles in the literature is challenging, not only because of heterogeneity in methodology, but also due to the variety of the scoring systems used to document clinical outcomes. There is limited information about the correlation between used scores and quality of life with no information being available on the impact of each score on the utility values. The aim of this study was to compare the most commonly used scores for evaluating patients with anterior cruciate ligament (ACL) injuries, and to establish corresponding utility values. These values will be used for the interpretation and comparison of outcome results in the currently available literature for different treatment options. METHODS: Four hypothetical vignettes were defined, based on different levels of activities after rupture of the ACL to simulate typical situations seen in daily practice. A questionnaire, including the Health Utility Index (HUI) for utility values, the IKDC subjective score, the Lysholm and the Tegner score, was created and 25 orthopedic surgeons were asked to fill the questionnaire for each hypothetical patient as proxies for all patients they had treated and who would fit in that hypothetical vignette. RESULTS: The utility value as an indicator for quality of life increased with the level of activity. Having discomforts already during normal activities of daily living was rated with a mean utility value of 0.37 ± 0.19, half of that of a situation where mild sport activity was possible without discomfort (0.78 ± 0.11). All investigated scores were able to distinguish clearly (p < 0.05) between the hypothetical vignettes. However, the utility values correlated best with the IKDC subjective score (r = 0.86, p < 0.001) followed by the Lysholm score (r = 0.77, p < 0.001) and the Tegner score (r = 0.77, p < 0.001). CONCLUSIONS: Here we report the correlation between the most commonly used scores for the assessment of patients with a ruptured ACL and utility values as an indicator of quality of life. Assumptions were based on expert opinions to provide a possible transformation algorithm. The IKDC subjective knee score showed the highest correlation to the quality of life (i.e. HUI) in patients with a ruptured ACL. Confirmation of our results is needed by systematic inclusion of a measurement instrument for utility values in future clinical studies beside the already used clinical knee scoring systems

Movements of Diadromous Fish in Large Unregulated Tropical Rivers Inferred from Geochemical Tracers

Patterns of migration and habitat use in diadromous fishes can be highly variable among individuals. Most investigations into diadromous movement patterns have been restricted to populations in regulated rivers, and little information exists for those in unregulated catchments. We quantified movements of migratory barramundi Lates calcarifer (Bloch) in two large unregulated rivers in northern Australia using both elemental (Sr/Ba) and isotope (87Sr/86Sr) ratios in aragonitic ear stones, or otoliths. Chemical life history profiles indicated significant individual variation in habitat use, particularly among chemically distinct freshwater habitats within a catchment. A global zoning algorithm was used to quantify distinct changes in chemical signatures across profiles. This algorithm identified between 2 and 6 distinct chemical habitats in individual profiles, indicating variable movement among habitats. Profiles of 87Sr/86Sr ratios were notably distinct among individuals, with highly radiogenic values recorded in some otoliths. This variation suggested that fish made full use of habitats across the entire catchment basin. Our results show that unrestricted movement among freshwater habitats is an important component of diadromous life histories for populations in unregulated systems

External versus internal fixation for bicondylar tibial plateau fractures: systematic review and meta-analysis.

BACKGROUND: It is uncertain whether external fixation or open reduction internal fixation (ORIF) is optimal for patients with bicondylar tibial plateau fractures. MATERIALS AND METHODS: A systematic review using Ovid MEDLINE, Embase Classic, Embase, AMED, the Cochrane Library, Open Grey, Orthopaedic Proceedings, WHO International Clinical Trials Registry Platform, Current Controlled Trials, US National Institute for Health Trials Registry, and the Cochrane Central Register of Controlled Trials. The search was conducted on 3rd October 2014 and no language limits were applied. Inclusion criteria were all clinical study designs comparing external fixation with open reduction internal fixation of bicondylar tibial plateau fractures. Studies of only one treatment modality were excluded, as were those that included unicondylar tibial plateau fractures. Treatment effects from studies reporting dichotomous outcomes were summarised using odds ratios. Continuous outcomes were converted to standardized mean differences to assess the treatment effect, and inverse variance methods used to combine data. A fixed effect model was used for meta-analyses. RESULTS: Patients undergoing external fixation were more likely to have returned to preinjury activities by six and twelve months (P = 0.030) but not at 24 months follow-up. However, external fixation was complicated by a greater number of infections (OR 2.59, 95 % CI 1.25-5.36, P = 0.01). There were no statistically significant differences in the rates of deep infection, venous thromboembolism, compartment syndrome, or need for re-operation between the two groups. CONCLUSION: Although external fixation and ORIF are associated with different complication profiles, both are acceptable strategies for managing bicondylar tibial plateau fractures

Rapid detection of pandemic influenza in the presence of seasonal influenza

Background: Key to the control of pandemic influenza are surveillance systems that raise alarms rapidly and sensitively. In addition, they must minimise false alarms during a normal influenza season. We develop a method that uses historical syndromic influenza data from the existing surveillance system 'SERVIS' (Scottish Enhanced Respiratory Virus Infection Surveillance) for influenza-like illness (ILI) in Scotland. Methods: We develop an algorithm based on the weekly case ratio (WCR) of reported ILI cases to generate an alarm for pandemic influenza. From the seasonal influenza data from 13 Scottish health boards, we estimate the joint probability distribution of the country-level WCR and the number of health boards showing synchronous increases in reported influenza cases over the previous week. Pandemic cases are sampled with various case reporting rates from simulated pandemic influenza infections and overlaid with seasonal SERVIS data from 2001 to 2007. Using this combined time series we test our method for speed of detection, sensitivity and specificity. Also, the 2008-09 SERVIS ILI cases are used for testing detection performances of the three methods with a real pandemic data. Results: We compare our method, based on our simulation study, to the moving-average Cumulative Sums (Mov-Avg Cusum) and ILI rate threshold methods and find it to be more sensitive and rapid. For 1% case reporting and detection specificity of 95%, our method is 100% sensitive and has median detection time (MDT) of 4 weeks while the Mov-Avg Cusum and ILI rate threshold methods are, respectively, 97% and 100% sensitive with MDT of 5 weeks. At 99% specificity, our method remains 100% sensitive with MDT of 5 weeks. Although the threshold method maintains its sensitivity of 100% with MDT of 5 weeks, sensitivity of Mov-Avg Cusum declines to 92% with increased MDT of 6 weeks. For a two-fold decrease in the case reporting rate (0.5%) and 99% specificity, the WCR and threshold methods, respectively, have MDT of 5 and 6 weeks with both having sensitivity close to 100% while the Mov-Avg Cusum method can only manage sensitivity of 77% with MDT of 6 weeks. However, the WCR and Mov-Avg Cusum methods outperform the ILI threshold method by 1 week in retrospective detection of the 2009 pandemic in Scotland. Conclusions: While computationally and statistically simple to implement, the WCR algorithm is capable of raising alarms, rapidly and sensitively, for influenza pandemics against a background of seasonal influenza. Although the algorithm was developed using the SERVIS data, it has the capacity to be used at other geographic scales and for different disease systems where buying some early extra time is critical

Challenges for IT-Enabled Formative Assessment of Complex 21st Century Skills

In this article, we identify and examine opportunities for formative assessment provided by information technologies (IT) and the challenges which these opportunities present. We address some of these challenges by examining key aspects of assessment processes that can be facilitated by IT: datafication of learning; feedback and scaffolding; peer assessment and peer feedback. We then consider how these processes may be applied in relation to the assessment of horizontal, general complex 21st century skills (21st CS), which are still proving challenging to incorporate into curricula as well as to assess. 21st CS such as creativity, complex problem solving, communication, collaboration and self-regulated learning contain complex constructs incorporating motivational and affective components. Our analysis has enabled us to make recommendations for policy, practice and further research. While there is currently much interest in and some progress towards the development of learning/assessment analytics for assessing 21st CS, the complexity of assessing such skills, together with the need to include affective aspects means that using IT-enabled techniques will need to be combined with more traditional methods of teacher assessment as well as peer assessment for some time to come. Therefore learners, teachers and school leaders must learn how to manage the greater variety of sorts and sources of feedback including resolving tensions of inconsistent feedback from different sources