Cell death mechanism in an isolated wood smoke inhalation induced-ARDS large animal model

Acute respiratory distress syndrome (ARDS) is a lethal disease condition in critically ill patients with a reported mortality rate reaching 45%. The current treatment modalities available for severe ARDS are invasive and carry significant risk for patients. Most published studies involving smoke inhalation utilize another simultaneous injury (such as cutaneous burn) to increase pathology burden of their animal models. This introduces confounding variables to investigations which aim to concentrate on inhalation injury. In this study, we evaluated the potential molecular targets associated with isolated smoke inhalation-induced ARDS. We observed an increase in lung injury score and wet/dry ratio 48h post smoke inhalation together with upregulation of inflammatory markers, IL-1βand IL-6 levels. Furthermore, there was a decrease in phosphorylation of cell survival marker Akt and an increase in pro-apoptotic protein BAX at 48h post smoke inhalation. These results indicate that smoke inhalation induced inflammatory processes resulting in increased apoptosis and decreased cell survival in lung parenchymal cells. Use of this unique model may be of benefit in studying the pathophysiology of inhalation injury and for the development of novel therapeutic strategies.https://digitalcommons.unmc.edu/surp2021/1045/thumbnail.jp

Paediatric fractures of carpal bones other than the scaphoid

OBJECTIVES Fractures of carpal bones other than the scaphoid are rare in children. The aim of this study was to analyze results and identify risk factors for an unfavorable outcome. MATERIAL AND METHODS Children and adolescents up to the age of 16 years who sustained a carpal fracture other than in the scaphoid between 2004 and 2021 were reviewed in this single-center retrospective study. RESULTS In a series of 209 children and adolescents with carpal fractures, 22 had fractures other than the scaphoid. Mean age was 13 years (range 8-16) years, with a total of 41 fractures, with highest incidences for the capitate (10), trapezium (6), triquetrum (4) and pisiform (4). Twenty-nine of these 41 fractures were missed on initial X-ray. Non-displaced fractures were treated with a short arm spica cast including the thumb. Four patients were operated on for displacement fracture or carpometacarpal subluxation. All fractures united, and patients returned to full activities. At the final consultation at a median 14 months (range 6-89) post-injury, all patients with non-displaced fractures were free of symptoms, with excellent Mayo Wrist Scores (MWS). However, three patients with operated trapezium fractures developed early radiological signs of osteoarthritis, two of them with residual pain and MWS rated only good. CONCLUSION Non-displaced pediatric carpal fractures treated by forearm cast have excellent prognosis. Fractures of the trapezium with displacement or first carpometacarpal subluxation incur a risk of osteoarthritis despite anatomical reduction and internal fixation

Legitimacy in conflict: concepts, practices, challenges

The study of legitimacy in situations of conflict and peacebuilding has increased in recent years. However, current work on the topic adopts many assumptions, definitions, and understandings from classical legitimacy theory, which centers on the relationship between the nation-state and its citizens. In this introduction, we provide a detailed critical overview of current theories of legitimacy and legitimation and demonstrate why they have only limited applicability in conflict and post-conflict contexts, focusing on the three main areas that the articles included in this special issue examine: audiences for legitimacy, sources of legitimacy, and legitimation. In particular, we show how conflict and post-conflict contexts are marked by the fragmentation and personalization of power; the proliferation and fragmentation of legitimacy audiences; and ambiguity surrounding legitimation strategies

Nominal or Real? The Impact of Regional Price Levels on Satisfaction with Life

According to economic theory, real income, i.e., nominal income adjusted for purchasing power, should be the relevant source of life satisfaction. Previous work, however, has only studied the impact of inflation adjusted nominal income and not taken into account regional differences in purchasing power. Therefore, we use a novel data set to study how regional price levels affect satisfaction with life. The data set comprises about 7 million data points that are used to construct a price level for each of the 428 administrative districts in Germany. We estimate pooled OLS and ordered probit models that include a comprehensive set of individual level, time-varying and time-invariant control variables as well as control variables that capture district heterogeneity other than the price level. Our results show that higher price levels significantly reduce life satisfaction. Furthermore, we find that a higher price level tends to induce a larger loss in life satisfaction than a corresponding decrease in nominal income. A formal test of neutrality of money, however, does not reject neutrality of money. Our results provide an argument in favor of regional indexation of government transfer payments such as social welfare benefits

Ciclosporin A Proof of Concept Study in Patients with Active, Progressive HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis

HTLV-1 is a retrovirus transmitted through body fluids that is commonly seen in the West Indies, South America and Southern Japan but rarely in the UK. Although most patients remain healthy carriers, HTLV-1 causes serious conditions such as adult T cell leukaemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/Tropical Spastic Paraparesis (HAM/TSP). The infection which is life-long cannot be eradicated and treatments for the associated diseases are limited. We report the encouraging findings of the first UK Medical Research Council funded treatment study for patients with early and/or deteriorating HAM/TSP. Treatment with ciclosporin A, a drug commonly used to dampen the immune system in transplant patients, was investigated. Symptoms and signs of disease, particularly low back pain and muscle stiffness, improved by week 24 and in some patients this improvement persisted after the 48 weeks of treatment, at least to the end of the study at week 72. Most striking was the finding that the amount of HTLV-1 in the fluid around the spinal cord, called cerebrospinal fluid, was reduced during treatment. These findings justify the further study of ciclosporin A in patients with HAM/TSP

Structured Observations Reveal Slow HIV-1 CTL Escape

The existence of viral variants that escape from the selection pressures imposed by cytotox- ic T-lymphocytes (CTLs) in HIV-1 infection is well documented, but it is unclear when they arise, with reported measures of the time to escape in individuals ranging from days to years. A study of participants enrolled in the SPARTAC (Short Pulse Anti-Retroviral Thera- py at HIV Seroconversion) clinical trial allowed direct observation of the evolution of CTL es- cape variants in 125 adults with primary HIV-1 infection observed for up to three years. Patient HLA-type, longitudinal CD8+ T-cell responses measured by IFN- γ ELISpot and lon- gitudinal HIV-1 gag , pol , and nef sequence data were used to study the timing and preva- lence of CTL escape in the participants whilst untreated. Results showed that sequence variation within CTL epitopes at the first time point (within six months of the estimated date of seroconversion) was consistent with most mutations being transmitted in the infecting viral strain rather than with escape arising within the first few weeks of infection. Escape arose throughout the first three years of infection, but slowly and steadily. Approximately one third of patients did not drive any new escape in an HLA-restricted epitope in just under two years. Patients driving several escape mutations during these two years were rare and the median and modal numbers of new escape events in each patient were one and zero re- spectively. Survival analysis of time to escape found that possession of a protective HLA type significantly reduced time to first escape in a patient (p = 0.01), and epitopes escaped faster in the face of a measurable CD8+ ELISpot response (p = 0.001). However, even in an HLA matched host who mounted a measurable, specific, CD8+ response the average time before the targeted epitope evolved an escape mutation was longer than two year

Pyocin S5 import into Pseudomonas aeruginosa reveals a generic mode of bacteriocin transport

Pyocin S5 (PyoS5) is a potent protein bacteriocin that eradicates the human pathogen Pseudomonas aeruginosa in animal infection models, but its import mechanism is poorly understood. Here, using crystallography, biophysical and biochemical analyses, and live-cell imaging, we define the entry process of PyoS5 and reveal links to the transport mechanisms of other bacteriocins. In addition to its C-terminal pore-forming domain, elongated PyoS5 comprises two novel tandemly repeated kinked 3-helix bundle domains that structure-based alignments identify as key import domains in other pyocins. The central domain binds the lipid-bound common polysaccharide antigen, allowing the pyocin to accumulate on the cell surface. The N-terminal domain binds the ferric pyochelin transporter FptA while its associated disordered region binds the inner membrane protein TonB1, which together drive import of the bacteriocin across the outer membrane. Finally, we identify the minimal requirements for sensitizing Escherichia coli toward PyoS5, as well as other pyocins, and suggest that a generic pathway likely underpins the import of all TonB-dependent bacteriocins across the outer membrane of Gram-negative bacteria