Managing Injuries of the Neck Trial (MINT) : design of a randomised controlled trial of treatments for whiplash associated disorders

Background: A substantial proportion of patients with whiplash injuries develop chronic symptoms. However, the best treatment of acute injuries to prevent long-term problems is uncertain. A stepped care treatment pathway has been proposed, in which patients are given advice and education at their initial visit to the emergency department (ED), followed by review at three weeks and physiotherapy for those with persisting symptoms. MINT is a two-stage randomised controlled trial to evaluate two components of such a pathway: 1. use of The Whiplash Book versus usual advice when patients first attend the emergency department; 2. referral to physiotherapy versus reinforcement of advice for patients with continuing symptoms at three weeks. Methods: Evaluation of the Whiplash Book versus usual advice uses a cluster randomised design in emergency departments of eight NHS Trusts. Eligible patients are identified by clinicians in participating emergency departments and are sent a study questionnaire within a week of their ED attendance. Three thousand participants will be included. Patients with persisting symptoms three weeks after their ED attendance are eligible to join an individually randomised study of physiotherapy versus reinforcement of the advice given in ED. Six hundred participants will be randomised. Follow-up is at 4, 8 and 12 months after their ED attendance. Primary outcome is the Neck Disability Index (NDI), and secondary outcomes include quality of life and time to return to work and normal activities. An economic evaluation is being carried out. Conclusion: This paper describes the protocol and operational aspects of a complex intervention trial based in NHS emergency and physiotherapy departments, evaluating two components of a stepped-care approach to the treatment of whiplash injuries. The trial uses two randomisations, with the first stage being cluster randomised and the second individually randomised

Growth and Differentiation of the Larval Mosquito Midgut

Factors affecting larval growth and nutrition have consequences on adult fecundity. Since the mosquito larval midgut is the primary organ of digestion and nutrient absorption, factors that affect the growth and development of the midgut may have potential consequences on the reproductive potential of the adult. To gain a better understanding of mosquito midgut development the growth and metamorphic remodeling of the Aedes aegypti L. and Culex pipiens L. (Diptera: Culicidae) midguts were investigated. Cytological evidence was obtained suggesting that, in both the anterior and posterior Ae. aegypti larval midgut, diploid regenerative cells give rise to new endoreplicating cells that significantly contribute to the growth and metabolism of the midgut. This hypothesis was supported by BrdU incorporation studies showing that diploid cells, as well as large and small endoreplicating cells, synthesize DNA during the 2nd, 3rd and 4th instars. Cytological studies of the Cx. pipiens larval midgut suggest that anterior midgut growth in this species is primarily by cell enlargement. To study metamorphic remodeling of the midgut, DNA synthesis in Ae. aegypti 4th instar midguts was followed by using 5-bromo-2-deoxyuridine (BrdU) incorporation. During the 24 hr period after the last larval-larval molt both endoreplicating and diploid cells incorporate BrdU. After the critical weight is achieved, endoreplicating cell BrdU incorporation gradually ceases while diploid cells continue to replicate. The period of maximum diploid cell incorporation correlated with the period of maximum ecdysone titer

Spatial heterogeneity of habitat suitability for Rift Valley fever occurrence in Tanzania: an ecological niche modelling approach

Despite the long history of Rift Valley fever (RVF) in Tanzania, extent of its suitable habitat in the country remains unclear. In this study we investigated potential effects of temperature, precipitation, elevation, soil type, livestock density, rainfall pattern, proximity to wild animals, protected areas and forest on the habitat suitability for RVF occurrence in Tanzania. Presence-only records of 193 RVF outbreak locations from 1930 to 2007 together with potential predictor variables were used to model and map the suitable habitats for RVF occurrence using ecological niche modelling. Ground-truthing of the model outputs was conducted by comparing the levels of RVF virus specific antibodies in cattle, sheep and goats sampled from locations in Tanzania that presented different predicted habitat suitability values. Habitat suitability values for RVF occurrence were higher in the northern and central-eastern regions of Tanzania than the rest of the regions in the country. Soil type and precipitation of the wettest quarter contributed equally to habitat suitability (32.4% each), followed by livestock density (25.9%) and rainfall pattern (9.3%). Ground-truthing of model outputs revealed that the odds of an animal being seropositive for RVFV when sampled from areas predicted to be most suitable for RVF occurrence were twice the odds of an animal sampled from areas least suitable for RVF occurrence (95% CI: 1.43, 2.76, p < 0.001). The regions in the northern and central-eastern Tanzania were more suitable for RVF occurrence than the rest of the regions in the country. The modelled suitable habitat is characterised by impermeable soils, moderate precipitation in the wettest quarter, high livestock density and a bimodal rainfall pattern. The findings of this study should provide guidance for the design of appropriate RVF surveillance, prevention and control strategies which target areas with these characteristics

The zinc finger domain of Wilms' tumor 1 suppressor gene (WT1) behaves as a dominant negative, leading to abrogation of WT1 oncogenic potential in breast cancer cells

Abstract Introduction There is growing evidence that the Wilms' tumor 1 suppressor gene (WT1) behaves as an oncogene in some forms of breast cancer. Previous studies have demonstrated that the N-terminal domain of WT1 can act as a dominant negative through self-association. In the studies presented here we have explored the potential for the zinc finger domain (ZF) of WT1 to also have dominant-negative effects, and thus further our understanding of this protein. Methods Using full-length and ZF-only forms of WT1 we assessed their effect on the WT1 and c-myc promoter using luciferase and chromatin immunoprecipitation assays. The gene expression levels were determined by quantitative real-time RT-PCR, northern blot and western blot. We also assessed the effect of the ZF-only form on the growth of breast cancer cell lines in culture. Results Transfection with WT1–ZF plasmids resulted in a stronger inhibition of WT1 promoter than full-length WT1 in breast cancer cells. The WT1–ZF form lacking the lysine–threonine–serine (KTS) insert (ZF - KTS) can bind to the majority of WT1 consensus sites throughout the WT1 promoter region, while the ZF containing the insert (ZF + KTS) form only binds to sites in the proximal promoter. The abundances of endogenous WT1 mRNA and protein were markedly decreased following the stable expression of ZF - KTS in breast cancer cells. The expressions of WT1 target genes, including c-myc, Bcl-2, amphiregulin and TERT, were similarly suppressed by ZF - KTS. Moreover, WT1–ZF - KTS abrogated the transcriptional activation of c-myc mediated by all four predominant isoforms of WT1 (including or lacking alternatively spliced exons 5 and 9). Finally, WT1–ZF - KTS inhibited colony formation and cell division, but induced apoptosis in MCF-7 cells. Conclusion Our observations strongly argue that the WT1–ZF plasmid behaves as a dominant-negative regulator of the endogenous WT1 in breast cancer cells. The inhibition on proliferation of breast cancer cells by WT1–ZF - KTS provides a potential candidate of gene therapy for breast cancer

Innate Immune Function in Placenta and Cord Blood of Hepatitis C – Seropositive Mother-Infant Dyads

Vertical transmission accounts for the majority of pediatric cases of hepatitis C viral (HCV) infection. In contrast to the adult population who develop persistent viremia in ∼80% of cases following exposure, the rate of mother-to-child transmission (2–6%) is strikingly low. Protection from vertical transmission likely requires the coordination of multiple components of the immune system. Placenta and decidua provide a direct connection between mother and infant. We hypothesized that innate immune responses would differ across the three compartments (decidua, placenta and cord blood) and that hepatitis C exposure would modify innate immunity in these tissues. The study was comprised of HCV-infected and healthy control mother and infant pairs from whom cord blood, placenta and decidua were collected with isolation of mononuclear cells. Multiparameter flow cytometry was performed to assess the phenotype, intracellular cytokine production and cytotoxicity of the cells. In keeping with a model where the maternal-fetal interface provides antiviral protection, we found a gradient in proportional frequencies of NKT and γδ-T cells being higher in placenta than cord blood. Cytotoxicity of NK and NKT cells was enhanced in placenta and placental NKT cytotoxicity was further increased by HCV infection. HCV exposure had multiple effects on innate cells including a decrease in activation markers (CD69, TRAIL and NKp44) on NK cells and a decrease in plasmacytoid dendritic cells in both placenta and cord blood of exposed infants. In summary, the placenta represents an active innate immunological organ that provides antiviral protection against HCV transmission in the majority of cases; the increased incidence in preterm labor previously described in HCV-seropositive mothers may be related to enhanced cytotoxicity of NKT cells

Climate Change and Risk of Leishmaniasis in North America: Predictions from Ecological Niche Models of Vector and Reservoir Species

Camila González is with National Autonomous University of Mexico, Ophelia Wang is with UT Austin, Stavana E. Strutz is with UT Austin, Constantino González-Salazar is with National Autonomous University of Mexico, Víctor Sánchez-Cordero is with National Autonomous University of Mexico, Sahotra Sarkar is with UT Austin.Background -- Climate change is increasingly being implicated in species' range shifts throughout the world, including those of important vector and reservoir species for infectious diseases. In North America (México, United States, and Canada), leishmaniasis is a vector-borne disease that is autochthonous in México and Texas and has begun to expand its range northward. Further expansion to the north may be facilitated by climate change as more habitat becomes suitable for vector and reservoir species for leishmaniasis. Methods and Findings -- The analysis began with the construction of ecological niche models using a maximum entropy algorithm for the distribution of two sand fly vector species (Lutzomyia anthophora and L. diabolica), three confirmed rodent reservoir species (Neotoma albigula, N. floridana, and N. micropus), and one potential rodent reservoir species (N. mexicana) for leishmaniasis in northern México and the United States. As input, these models used species' occurrence records with topographic and climatic parameters as explanatory variables. Models were tested for their ability to predict correctly both a specified fraction of occurrence points set aside for this purpose and occurrence points from an independently derived data set. These models were refined to obtain predicted species' geographical distributions under increasingly strict assumptions about the ability of a species to disperse to suitable habitat and to persist in it, as modulated by its ecological suitability. Models successful at predictions were fitted to the extreme A2 and relatively conservative B2 projected climate scenarios for 2020, 2050, and 2080 using publicly available interpolated climate data from the Third Intergovernmental Panel on Climate Change Assessment Report. Further analyses included estimation of the projected human population that could potentially be exposed to leishmaniasis in 2020, 2050, and 2080 under the A2 and B2 scenarios. All confirmed vector and reservoir species will see an expansion of their potential range towards the north. Thus, leishmaniasis has the potential to expand northwards from México and the southern United States. In the eastern United States its spread is predicted to be limited by the range of L. diabolica; further west, L. anthophora may play the same role. In the east it may even reach the southern boundary of Canada. The risk of spread is greater for the A2 scenario than for the B2 scenario. Even in the latter case, with restrictive (contiguous) models for dispersal of vector and reservoir species, and limiting vector and reservoir species occupancy to only the top 10% of their potential suitable habitat, the expected number of human individuals exposed to leishmaniasis by 2080 will at least double its present value. Conclusions -- These models predict that climate change will exacerbate the ecological risk of human exposure to leishmaniasis in areas outside its present range in the United States and, possibly, in parts of southern Canada. This prediction suggests the adoption of measures such as surveillance for leishmaniasis north of Texas as disease cases spread northwards. Potential vector and reservoir control strategies—besides direct intervention in disease cases—should also be further investigated.This study was partially supported by the Universidad Nacional Autonoma de Mexico (Project PAPIIT IN 225408). CG was a recipient of the Dirección General de Estudios de Posgrado fellowship for the Posgrado en Ciencias Biomédicas, Facultad de Medicina, Universidad Nacional Autónoma de México. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Biological Sciences, School o

Effects of Specific Multi-Nutrient Enriched Diets on Cerebral Metabolism, Cognition and Neuropathology in AbetaPPswe-PS1dE9 Mice

Contains fulltext : 119269.pdf (publisher's version ) (Open Access)Recent studies have focused on the use of multi-nutrient dietary interventions in search of alternatives for the treatment and prevention of Alzheimer's disease (AD). In this study we investigated to which extent long-term consumption of two specific multi-nutrient diets can modulate AD-related etiopathogenic mechanisms and behavior in 11-12-month-old AbetaPPswe-PS1dE9 mice. Starting from 2 months of age, male AbetaPP-PS1 mice and wild-type littermates were fed either a control diet, the DHA+EPA+UMP (DEU) diet enriched with uridine monophosphate (UMP) and the omega-3 fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), or the Fortasyn(R) Connect (FC) diet enriched with the DEU diet plus phospholipids, choline, folic acid, vitamins and antioxidants. We performed behavioral testing, proton magnetic resonance spectroscopy, immunohistochemistry, biochemical analyses and quantitative real-time PCR to gain a better understanding of the potential mechanisms by which these multi-nutrient diets exert protective properties against AD. Our results show that both diets were equally effective in changing brain fatty acid and cholesterol profiles. However, the diets differentially affected AD-related pathologies and behavioral measures, suggesting that the effectiveness of specific nutrients may depend on the dietary context in which they are provided. The FC diet was more effective than the DEU diet in counteracting neurodegenerative aspects of AD and enhancing processes involved in neuronal maintenance and repair. Both diets elevated interleukin-1beta mRNA levels in AbetaPP-PS1 and wild-type mice. The FC diet additionally restored neurogenesis in AbetaPP-PS1 mice, decreased hippocampal levels of unbound choline-containing compounds in wild-type and AbetaPP-PS1 animals, suggesting diminished membrane turnover, and decreased anxiety-related behavior in the open field behavior. In conclusion, the current data indicate that specific multi-nutrient diets can influence AD-related etiopathogenic processes. Intervention with the FC diet might be of interest for several other neurodegenerative and neurological disorders