Coagulation and coagulation signalling in fibrosis

AbstractFollowing tissue injury, a complex and coordinated wound healing response comprising coagulation, inflammation, fibroproliferation and tissue remodelling has evolved to nullify the impact of the original insult and reinstate the normal physiological function of the affected organ. Tissue fibrosis is thought to result from a dysregulated wound healing response as a result of continual local injury or impaired control mechanisms. Although the initial insult is highly variable for different organs, in most cases, uncontrolled or sustained activation of mesenchymal cells into highly synthetic myofibroblasts leads to the excessive deposition of extracellular matrix proteins and eventually loss of tissue function. Coagulation was originally thought to be an acute and transient response to tissue injury, responsible primarily for promoting haemostasis by initiating the formation of fibrin plugs to enmesh activated platelets within the walls of damaged blood vessels. However, the last 20years has seen a major re-evaluation of the role of the coagulation cascade following tissue injury and there is now mounting evidence that coagulation plays a critical role in orchestrating subsequent inflammatory and fibroproliferative responses during normal wound healing, as well as in a range of pathological contexts across all major organ systems. This review summarises our current understanding of the role of coagulation and coagulation initiated signalling in the response to tissue injury, as well as the contribution of uncontrolled coagulation to fibrosis of the lung, liver, kidney and heart. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease

Vulnerability of Subsistence Systems Due to Social and Environmental Change: A Case Study in the Yukon-Kuskokwim Delta, Alaska

Arctic Indigenous communities have been classified as highly vulnerable to climate change impacts. The remoteness of Arctic communities, their dependence upon local species and habitats, and the historical marginalization of Indigenous peoples enhances this characterization of vulnerability. However, vulnerability is a result of diverse historical, social, economic, political, cultural, institutional, natural resource, and environmental conditions and processes and is not easily reduced to a single metric. Furthermore, despite the widespread characterization of vulnerability, Arctic Indigenous communities are extremely resilient as evidenced by subsistence institutions that have been developed over thousands of years. We explored the vulnerability of subsistence systems in the Cup’ik village of Chevak and Yup’ik village of Kotlik through the lens of the strong seasonal dimensions of resource availability. In the context of subsistence harvesting in Alaska Native villages, vulnerability may be determined by analyzing the exposure of subsistence resources to climate change impacts, the sensitivity of a community to those impacts, and the capacity of subsistence institutions to absorb these impacts. Subsistence resources, their seasonality, and perceived impacts to these resources were investigated via semi-structured interviews and participatory mapping-calendar workshops. Results suggest that while these communities are experiencing disproportionate impacts of climate change, Indigenous ingenuity and adaptability provide an avenue for culturally appropriate adaptation strategies. However, despite this capacity for resiliency, rapid socio-cultural changes have the potential to be a barrier to community adaptation and the recent, ongoing shifts in seasonal weather patterns may make seasonally specific subsistence adaptations to landscape particularly vulnerable.Les collectivités autochtones de l’Arctique sont classées comme étant fortement vulnérables aux incidences du changement climatique. L’éloignement des collectivités de l’Arctique, leur dépendance des espèces et des habitats locaux de même que la marginalisation historique des peuples autochtones intensifient cette vulnérabilité. Toutefois, la vulnérabilité est le résultat de conditions et de processus divers sur le plan historique, social, économique, politique, culturel, institutionnel, environnemental et des ressources naturelles. Il est difficile d’attribuer la vulnérabilité à un seul aspect. Malgré cette vaste caractérisation de la vulnérabilité, les collectivités autochtones de l’Arctique sont extrêmement résilientes, comme en attestent les modes de subsistance qui se sont développés au fil de milliers d’années. Nous avons exploré la vulnérabilité des systèmes de subsistance du village cup’ik de Chevak et du village yup’ik de Kotlik du point de vue des dimensions saisonnières fortes de la disponibilité des ressources. Dans le contexte des récoltes de subsistance des villages autochtones de l’Alaska, la vulnérabilité peut être déterminée au moyen de l’exposition des ressources de subsistance aux incidences du changement climatique, de la sensibilité d’une collectivité à ces incidences et de la capacité des institutions de subsistance à absorber ces incidences. Les ressources de subsistance, leur saisonnalité et les incidences perçues de ces ressources ont été étudiées au moyen d’entrevues semi-structurées et d’ateliers participatifs d’établissement de calendrier. Selon les résultats, bien que ces collectivités soient aux prises avec des incidences disproportionnées de changement climatique, l’ingéniosité et l’adaptabilité des Autochtones pavent le chemin à des stratégies d’adaptation convenant à leur culture. Cependant, malgré cette capacité de résilience, les changements socioculturels accélérés ont la possibilité de faire obstacle à l’adaptation collective, sans compter que la variation continue des tendances climatiques saisonnières peut rendre les adaptations de subsistance saisonnières au paysage particulièrement vulnérables

Safety Findings in Pediatric Patients During Long-Term Treatment With Teduglutide for Short-Bowel Syndrome-Associated Intestinal Failure : Pooled Analysis of 4 Clinical Studies

Background This analysis assessed combined safety data from 4 clinical studies of teduglutide in pediatric patients with short-bowel syndrome-associated intestinal failure (SBS-IF). Methods Safety data from teduglutide-treated patients in 4 clinical trials were pooled. The completed 12-week and 24-week phase 3 core studies (NCT01952080/EudraCT 2013-004588-30 and NCT02682381/EudraCT 2015-002252-27) enrolled children aged 1-17 years with SBS-IF. Patients could elect to enroll in ongoing open-label extensions (NCT02949362/EudraCT 2016-000863-17 and NCT02954458/EudraCT 2016-000849-30). Interim data from ongoing studies were included. Results Safety data are reported for 89 pediatric patients treated with teduglutide for a median (range) of 51.7 (5.0-94.7) weeks. Adverse events (AEs) were reported in all patients; the most common were vomiting (51.7%), pyrexia (43.8%), upper respiratory tract infection (41.6%), and cough (33.7%). Thirty-five patients (39.3%) had AEs considered related to teduglutide treatment; abdominal pain and vomiting were most frequent (5.6% each). Three serious AEs in 3 patients (3.4%) were considered related to teduglutide treatment: ileus, d-lactic acidosis, and gastrointestinal obstruction due to hard stools. All 3 events resolved. One cecal polyp was detected, which was not biopsied or found on repeat colonoscopy. No cases of neoplasia occurred. Conclusion Based on integrated data from 4 clinical studies, including long-term follow-up forPeer reviewe

Safety and Efficacy of Teduglutide in Pediatric Patients With Intestinal Failure due to Short Bowel Syndrome : A 24-Week, Phase III Study

Background This study evaluated the safety and efficacy of teduglutide in pediatric patients with short bowel syndrome-associated intestinal failure (SBS-IF). Methods A 24-week, phase III trial with 2 randomized, double-blind teduglutide dose groups and a nonblinded standard of care (SOC) arm was used; patients received 0.025 mg/kg or 0.05 mg/kg teduglutide once daily. Safety end points included treatment-emergent adverse events (TEAEs) and growth parameters. The primary efficacy/pharmacodynamic end point was the number of patients who achieved a >= 20% reduction in parenteral support (PS) from baseline at week 24. Results All 59 enrolled patients completed the study (0.025 mg/kg, n = 24; 0.05 mg/kg, n = 26; SOC, n = 9). Baseline demographics and disease characteristics were comparable among groups. TEAEs were reported by 98% and 100% of patients in the teduglutide and SOC groups, respectively. The most common TEAEs in the teduglutide-treated groups were pyrexia and vomiting. The primary end point was achieved by 13 (54.2%), 18 (69.2%), and 1 (11.1%) patients who received 0.025 mg/kg teduglutide, 0.05 mg/kg teduglutide, and SOC, respectively (P <0.05 vs SOC). Both 0.025-mg/kg and 0.05-mg/kg teduglutide groups showed clinically significant reductions in PS volume (P <0.05 vs SOC), PS calories, days per week and hours per day of PS infusions, and increases in enteral nutrition and plasma citrulline at week 24 compared with baseline. Two (8.3%, 0.025 mg/kg teduglutide) and 3 patients (11.5%, 0.05 mg/kg teduglutide) achieved enteral autonomy. Conclusion The safety profile of teduglutide was similar to that reported previously in children and adults. Treatment with teduglutide was associated with significant reductions in PS for pediatric patients with SBS-IF over 24 weeks.Peer reviewe

The influence of injector design on the decay of pre-ignition turbulence in a spherical explosion chamber

This paper reports on an experimental study to characterize the turbulent flow field inside a 20 l Siwek chamber during the preignition period. An acrylonitrile-butadiene-styrene model of the chamber was constructed with optical quality windows enabling laser Doppler anemometry (LDA) to be used for turbulence measurements. Alumina (Al 2 O 3 ) particles were used as the seed dust for measuring the gas-phase turbulence. Three specific dust dispersion systems have been investigated: (1) the deflector plate (also referred to as the rebound nozzle); (2) the perforated annular nozzle; and (3) the circular &quot;Dahoe&quot; nozzle. It is assumed that changing the method of dust dispersion alters the turbulence characteristics. The flow field is non-stationary, i.e., the mean (or predominant fluid flow) and superimposed velocity fluctuations upon the mean decrease with time. Furthermore, there are variations from injection to injection. A procedure has been developed to analyze this non-stationary signal to extract the mean and fluctuating components of velocity, thereby paving the way for decay &quot;laws&quot; to be determined for a particular nozzle configuration

"I try and smile, I try and be cheery, I try not to be pushy. I try to say ‘I’m here for help’ but I leave feeling… worried’’: A qualitative study of perceptions of interactions with health professionals by community-based older adults with chronic pain

Background: Over 50% of community-dwelling older adults experience chronic pain, which threatens their quality of life. Of importance to their pain management is older people’s interaction with health professionals that, if unsatisfactory, may impair the outcome. Aims: To add to the limited research specific to older people living with chronic pain in the community, we explored how they perceive their experiences of interacting with health professionals, seeking factors that might optimise these interactions. Methods: Purposive sampling was used to recruit men and women .65 years with self-reported musculoskeletal chronic pain. Qualitative individual interviews and one group interview were undertaken with 23 participants. Data were transcribed verbatim and underwent Framework Analysis. Results: Three themes were identified. Seeking help illustrates issues around why older people in the community may or may not seek help for chronic pain, and highlights the potential involvement of social comparison. Importance of diagnosis illustrates the desire for professional validation of their condition and an aversion to vague explanations based on the person’s age. Being listened to and being heard illustrates the importance of empathic communication and understanding expectations, with due respect for the person’s age. Conclusions: In common with people of all ages, an effective partnership between an older person in pain and health professionals is essential if pain is to be reported, appropriately assessed and managed, because of the subjective nature of pain and its treatment responses. For older people with pain, perception about their age, by both parties in the partnership, is an additional factor that can unnecessarily interfere with the effectiveness of this partnership. Health professionals should engage with older adults to clarify their expectations about pain and its management, which may be influenced by perceptions about age; and to encourage expression of their concerns, which may also be affected by perceptions about age

The circadian clock protein REVERBα inhibits pulmonary fibrosis development

Pulmonary inflammatory responses lie under circadian control; however, the importance of circadian mechanisms in the underlying fibrotic phenotype is not understood. Here, we identify a striking change to these mechanisms resulting in a gain of amplitude and lack of synchrony within pulmonary fibrotic tissue. These changes result from an infiltration of mesenchymal cells, an important cell type in the pathogenesis of pulmonary fibrosis. Mutation of the core clock protein REVERBα in these cells exacerbated the development of bleomycin-induced fibrosis, whereas mutation of REVERBα in club or myeloid cells had no effect on the bleomycin phenotype. Knockdown of REVERBα revealed regulation of the little-understood transcription factor TBPL1. Both REVERBα and TBPL1 altered integrinβ1 focal-adhesion formation, resulting in increased myofibroblast activation. The translational importance of our findings was established through analysis of 2 human cohorts. In the UK Biobank, circadian strain markers (sleep length, chronotype, and shift work) are associated with pulmonary fibrosis, making them risk factors. In a separate cohort, REVERBα expression was increased in human idiopathic pulmonary fibrosis (IPF) lung tissue. Pharmacological targeting of REVERBα inhibited myofibroblast activation in IPF fibroblasts and collagen secretion in organotypic cultures from IPF patients, thus suggesting that targeting of REVERBα could be a viable therapeutic approach

Examination of the Cytotoxic and Embryotoxic Potential and Underlying Mechanisms of Next-Generation Synthetic Trioxolane and Tetraoxane Antimalarials

Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria

I will not go, I cannot go: cultural and social limitations of disaster preparedness in Asia, Africa, and Oceania

While much work has been invested in addressing the economic and technical basis of disaster preparedness, less effort has been directed towards understanding the cultural and social obstacles to and opportunities for disaster risk reduction. This paper presents local insights from five different national settings into the cultural and social contexts of disaster preparedness. In most cases, an early warning system was in place, but it failed to alert people to diverse environmental shocks. The research findings show that despite geographical and typological differences in these locations, the limitations of the systems were fairly similar. In Kenya, people received warnings, but from contradictory systems, whereas in the Philippines and on the island of Saipan, people did not understand the messages or take them seriously. In Bangladesh and Nepal, however, a deeper cultural and religious reasoning serves to explain disasters, and how to prevent them or find safety when they strike