Crack modelling in power plant components

Much of the process plant designed in the early 1970s, in response to increased demandfor power, is now 'ageing' and necessitates an on-going fitness for service' assessment. This is necessary to satisfy licensing authorities requirements for continuous operations. Fitness for service assessment involves many issues including evaluation of structural flaws, material degradation, damage due to creep, fatigue and plasticity and the overall effect on the residual life of components. Codes of practice such as API 579, BS 7910 and R6 give detailed assessment procedures and may involve very detailed and time consuming finite element analyses. The authors have developed an FEA tool, Zencrack, to accurately evaluate single or multiple cracks in any structure (e.g. pressure vessels, piping, etc.). Further, 3D non planar crack growth under general fatigue or time dependent loading is possible. The software can help to increase efficiencyin performing sensitivity studies, thus allowing more accurateassessment of the residual life of the plant than would otherwise be possible in a given timeframe

The pediatric anti-viral immune response impairs neural stem/progenitor cell activity

The neuropathological outcomes of a viral infection in the brain are often age-dependent. Infection of the immature CNS can lead to impairment of neural/stem progenitor cell (NSPCs) activity. NSPCs are multi-potent progenitor cells of the CNS and are responsible for populating the brain with neurons, astrocytes, and oligodendrocytes during development. Viral infections may alter NSPC activity via two mechanisms; directly by infection of the NSPC or indirectly due to the anti-viral immune response. Here, we examined the impact of a neurotropic infection on NSPC activity in pediatric mice (postnatal day 10), where brain and immune system development is ongoing. In order to define how anti-viral immunity affected NSPC activity, we used a mouse model of neuron restricted measles virus (MV) infection, where the virus selectively infects mature neurons and NSPCs are spared from infection. Flow cytometric analysis on the hippocampus and sub-ventricular zone (SVZ) showed a significant reduction in NSPC numbers at 9 days post infection (dpi). Mature neurons were increased in both the hippocampus and SVZ at 9 dpi, while the SVZ alone showed a decrease in immature neurons at this time point. Innate (neutrophils, macrophage/microglia, NK cells) and adaptive immune cells (T and B cells) were significantly higher in the infected group at 9 dpi. The decline in the NSPC pool showed a strong negative correlation with immune cell infiltration in the brain. Our results suggest that pediatric NSPC pool contracts in different brain regions during a CNS viral infection, which may be indicative of NSPC death, inhibition of proliferation, or increased differentiation. Current studies aim to determine the mechanism behind NSPC cell loss early in infection and to define the long-term effects of viral infection on the NSPC pool in surviving mice

Pediatric Neurotropic Infection Alters Synaptic Development in the Developing Brain

Many neurotropic viruses cause more significant pathology in younger hosts as their brains are still developing. This experiment asked how central nervous system (CNS) viral-infections affect the development of synapses in the pediatric brain during infection and post-infection. Synaptogenesis is at its peak in pediatric mice (10 days old) and we hypothesized that a neurotropic infection could disrupt synaptic proteins. We used a transgenic mouse model where measles virus (MV) infects only mature neurons, leading us to question whether synapses were impacted. We examined synaptic markers in the cerebellum and hippocampus in MV-infected and uninfected mice 9 days and 90 days post-infection through western blot analysis. We found differential downregulation of pre-synaptic proteins (synapsins 1, 2 and 3) during infection, which was dependent on the brain region and the time point examined. This highlights the short and long-term consequences of a pediatric infection on neurodevelopment and potential dysregulation of synaptogenesis

Egr-1 induces DARPP-32 expression in striatal medium spiny neurons via a conserved intragenic element.

DARPP-32 (dopamine and adenosine 3\u27, 5\u27-cyclic monophosphate cAMP-regulated phosphoprotein, 32 kDa) is a striatal-enriched protein that mediates signaling by dopamine and other first messengers in the medium spiny neurons. The transcriptional mechanisms that regulate striatal DARPP-32 expression remain enigmatic and are a subject of much interest in the efforts to induce a striatal phenotype in stem cells. We report the identification and characterization of a conserved region, also known as H10, in intron IV of the gene that codes for DARPP-32 (Ppp1r1b). This DNA sequence forms multiunit complexes with nuclear proteins from adult and embryonic striata of mice and rats. Purification of proteins from these complexes identified early growth response-1 (Egr-1). The interaction between Egr-1 and H10 was confirmed in vitro and in vivo by super-shift and chromatin immunoprecipitation assays, respectively. Importantly, brain-derived neurotrophic factor (BDNF), a known inducer of DARPP-32 and Egr-1 expression, enhanced Egr-1 binding to H10 in vitro. Moreover, overexpression of Egr-1 in primary striatal neurons induced the expression of DARPP-32, whereas a dominant-negative Egr-1 blocked DARPP-32 induction by BDNF. Together, this study identifies Egr-1 as a transcriptional activator of the Ppp1r1b gene and provides insight into the molecular mechanisms that regulate medium spiny neuron maturation

Caspofungin Use in Daily Clinical Practice for Treatment of Invasive Aspergillosis: Results of a Prospective Observational Registry

<p>Abstract</p> <p>Background</p> <p>A prospective observational registry assessed real world experience with caspofungin monotherapy or combination therapy for the initial or salvage treatment of proven or probable invasive aspergillosis (IA).</p> <p>Methods</p> <p>Data were collected from April 2006 to September 2007 for patients treated with caspofungin for a single episode of IA. Clinical effectiveness was categorized as favorable (complete or partial) or unfavorable (stable disease or failure) at the end of caspofungin therapy (EOCT).</p> <p>Results</p> <p>Consecutive patients (n = 103) with proven or probable IA (per EORTC/MSG criteria) were identified from 11 countries. Malignancy (76.7%), neutropenia (64.1%), allogeneic hematopoietic stem cell transplantation (HSCT, 22.3%), solid organ transplantation (8.7%), autologous HSCT (4.9%), and HIV/AIDS (2.9%) were the most common underlying conditions. Most patients (84.5%) had pulmonary IA. <it>Aspergillus fumigatus </it>was the most frequently isolated species. The majority of patients received caspofungin monotherapy (82.5%) primarily as salvage therapy (82.4%). The main reason for switching to salvage therapy was clinical failure of the first-line therapy (69%). A favorable response at EOCT was seen in 56.4% (57/101) of patients overall, including 56.5% (48/85) and 56.3% (9/16) of patients receiving caspofungin monotherapy and combination therapy, respectively. Favorable response rates in clinically relevant subgroups were: malignancy, 51.9% (41/79); allogeneic HSCT, 56.5% (13/23); and neutropenia at time of hospitalization, 53.0% (35/66). There was a 72.3% (73/101) survival at 7 days after EOCT. Serious adverse events related to caspofungin were reported in 4 cases (3.9%); 3 patients (2.9%) discontinued treatment due to an adverse event related to caspofungin.</p> <p>Conclusions</p> <p>Caspofungin was both effective and well tolerated among high-risk patient groups such as those with neutropenia and active malignancies.</p

Safety perspectives on presently considered drugs for the treatment of COVID‐19

Intense efforts are underway to evaluate potential therapeutic agents for the treatment of COVID‐19. In order to respond quickly to the crisis, the repurposing of existing drugs is the primary pharmacological strategy. Despite the urgent clinical need for these therapies, it is imperative to consider potential safety issues. This is important due to the harm–benefit ratios that may be encountered when treating COVID‐19, which can depend on the stage of the disease, when therapy is administered and underlying clinical factors in individual patients. Treatments are currently being trialled for a range of scenarios from prophylaxis (where benefit must greatly exceed risk) to severe life‐threatening disease (where a degree of potential risk may be tolerated if it is exceeded by the potential benefit). In this perspective, we have reviewed some of the most widely researched repurposed agents in order to identify potential safety considerations using existing information in the context of COVID‐19

Immunodominance of HIV-1 Specific CD8+ T-Cell Responses Is Related to Disease Progression Rate in Vertically Infected Adolescents

BACKGROUND: HIV-1 vertically infected children in the USA are living into adolescence and beyond with the widespread use of antiretroviral drugs. These patients exhibit striking differences in the rate of HIV-1 disease progression which could provide insights into mechanisms of control. We hypothesized that differences in the pattern of immunodomination including breadth, magnitude and polyfunctionality of HIV-1 specific CD8+ T cell response could partially explain differences in progression rate. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we mapped, quantified, and assessed the functionality of these responses against individual HIV-1 Gag peptides in 58 HIV-1 vertically infected adolescents. Subjects were divided into two groups depending upon the rate of disease progression: adolescents with a sustained CD4%≥25 were categorized as having no immune suppression (NS), and those with CD4%≤15 categorized as having severe immune suppression (SS). We observed differences in the area of HIV-1-Gag to which the two groups made responses. In addition, subjects who expressed the HLA- B*57 or B*42 alleles were highly likely to restrict their immunodominant response through these alleles. There was a significantly higher frequency of naïve CD8+ T cells in the NS subjects (p = 0.0066) compared to the SS subjects. In contrast, there were no statistically significant differences in any other CD8+ T cell subsets. The differentiation profiles and multifunctionality of Gag-specific CD8+ T cells, regardless of immunodominance, also failed to demonstrate meaningful differences between the two groups. CONCLUSIONS/SIGNIFICANCE: Together, these data suggest that, at least in vertically infected adolescents, the region of HIV-1-Gag targeted by CD8+ T cells and the magnitude of that response relative to other responses may have more importance on the rate of disease progression than their qualitative effector functions