Cortisol levels and neuropsychiatric diagnosis as markers of postoperative delirium: a prospective cohort study

Polish Ministry of Science and Higher Education, Grant No. 0174/P01/2010/70; 504-06-011

A Lentivirus-Mediated Genetic Screen Identifies Dihydrofolate Reductase (DHFR) as a Modulator of β-Catenin/GSK3 Signaling

The multi-protein β-catenin destruction complex tightly regulates β-catenin protein levels by shuttling β-catenin to the proteasome. Glycogen synthase kinase 3β (GSK3β), a key serine/threonine kinase in the destruction complex, is responsible for several phosphorylation events that mark β-catenin for ubiquitination and subsequent degradation. Because modulation of both β-catenin and GSK3β activity may have important implications for treating disease, a complete understanding of the mechanisms that regulate the β-catenin/GSK3β interaction is warranted. We screened an arrayed lentivirus library expressing small hairpin RNAs (shRNAs) targeting 5,201 human druggable genes for silencing events that activate a β-catenin pathway reporter (BAR) in synergy with 6-bromoindirubin-3′oxime (BIO), a specific inhibitor of GSK3β. Top screen hits included shRNAs targeting dihydrofolate reductase (DHFR), the target of the anti-inflammatory compound methotrexate. Exposure of cells to BIO plus methotrexate resulted in potent synergistic activation of BAR activity, reduction of β-catenin phosphorylation at GSK3-specific sites, and accumulation of nuclear β-catenin. Furthermore, the observed synergy correlated with inhibitory phosphorylation of GSK3β and was neutralized upon inhibition of phosphatidyl inositol 3-kinase (PI3K). Linking these observations to inflammation, we also observed synergistic inhibition of lipopolysaccharide (LPS)-induced production of pro-inflammatory cytokines (TNFα, IL-6, and IL-12), and increased production of the anti-inflammatory cytokine IL-10 in peripheral blood mononuclear cells exposed to GSK3 inhibitors and methotrexate. Our data establish DHFR as a novel modulator of β-catenin and GSK3 signaling and raise several implications for clinical use of combined methotrexate and GSK3 inhibitors as treatment for inflammatory disease

Density functional theory

Density functional theory (DFT) finds increasing use in applications related to biological systems. Advancements in methodology and implementations have reached a point where predicted properties of reasonable to high quality can be obtained. Thus, DFT studies can complement experimental investigations, or even venture with some confidence into experimentally unexplored territory. In the present contribution, we provide an overview of the properties that can be calculated with DFT, such as geometries, energies, reaction mechanisms, and spectroscopic properties. A wide range of spectroscopic parameters is nowadays accessible with DFT, including quantities related to infrared and optical spectra, X-ray absorption and Mössbauer, as well as all of the magnetic properties connected with electron paramagnetic resonance spectroscopy except relaxation times. We highlight each of these fields of application with selected examples from the recent literature and comment on the capabilities and limitations of current methods

The Wnt-dependent signaling pathways as target in oncology drug discovery

Our current understanding of the Wnt-dependent signaling pathways is mainly based on studies performed in a number of model organisms including, Xenopus, Drosophila melanogaster, Caenorhabditis elegans and mammals. These studies clearly indicate that the Wnt-dependent signaling pathways are conserved through evolution and control many events during embryonic development. Wnt pathways have been shown to regulate cell proliferation, morphology, motility as well as cell fate. The increasing interest of the scientific community, over the last decade, in the Wnt-dependent signaling pathways is supported by the documented importance of these pathways in a broad range of physiological conditions and disease states. For instance, it has been shown that inappropriate regulation and activation of these pathways is associated with several pathological disorders including cancer, retinopathy, tetra-amelia and bone and cartilage disease such as arthritis. In addition, several components of the Wnt-dependent signaling pathways appear to play important roles in diseases such as Alzheimer’s disease, schizophrenia, bipolar disorder and in the emerging field of stem cell research. In this review, we wish to present a focused overview of the function of the Wnt-dependent signaling pathways and their role in oncogenesis and cancer development. We also want to provide information on a selection of potential drug targets within these pathways for oncology drug discovery, and summarize current data on approaches, including the development of small-molecule inhibitors, that have shown relevant effects on the Wnt-dependent signaling pathways

Gastric mucosal injury and repair, effect of aging

Although the gastric mucosa of healthy adult animals possesses the inherent capacity to promptly repair (often within 24 h) after a minor to moderate injury, aging appears to diminish its reparative capacity. At least two different repair mechanisms are thought to participate in full repair of the damaged gastric mucosa: the initial rapid process of mucosal restitution begins by migration of viable epithelial cells from gastric pits and glands; the subsequent slower process is replacement of lost cells by cell division. Intracellular events that regulate these processes are poorly understood, nor do we know how they may be affected by aging. However, evidence is accumulating which suggests that a number of gastrointestinal hormones/growth factors, most notably EGF and TGF-a may play a critica1 role in regulating gastric mucosal reparative processes. Since EGF and TGF-a exert their physiological actions by activating the intrinsic tyrosine kinase (Tyr-k) activity of their common receptor, the EGF-R, studies have been performed to assess the role of EGF-R Tyr-k in regulating mucosal reparative processes during aging. Recent data suggest that the age-related decline in mucosal repair after acute injury could in part be due to decreased activation of EGF-R Tyr-k. In addition, polyamines and prostaglandins are also thought to be involved in gastric mucosal reparative processes. Although the involvement of polyamines in gastric mucosal reparative processes during aging has not yet been studied, decreased mucosal prostaglandin levels in the aged are thought to be a causative factor for the increased susceptibility of the mucosa to injury. These and other relevant matters are discussed in the current review

Properties of thin anti-adhesive films used for the replication of microstructures in polymers

The aim of this work was to investigate the degradation of the anti-adhesive properties of protective PTFE films during the hot embossing of thermoplasts, and to identify possible failure causes which reduce the lifetime of these films. A comparative XPS study of different deposited films and embossing parameters resulted in a better understanding of the film/polymer interactions at high temperatures. The loss of fluorine was found to be a major cause of the film quality degradation. It resulted from the diffusion of fluorinated entities or small polymer chains from the film to the embossed material during the embossing process. This led us to make some suggestions for the optimization of the working parameters in the hot embossing technique

Willingness to Pay for a Treatment for Pain in Multiple Sclerosis

BackgroundBackground Multiple sclerosis (MS) is a chronic neurological disease that affects 240 per 100 000 Canadians. Of these patients, 10-80% (average 70%) experience pain. Sativex is a cannabis-based drug recently approved for neuropathic pain. Abstract: ObjectivesObjectives In this study, we determine individuals' preferences between two treatment options as well as the willingness to pay (WTP) for Sativex, expressed as the amount they would pay in insurance premiums to have access to that treatment. Abstract: MethodsMethods The WTP instrument comprised a decision board as a visual aid, and a questionnaire. A decision board helps clinicians standardize the presentation of treatment information. In this study, the decision board described two treatment options: a three-drug combination (gabapentin, amytriptyline, acetaminophen [paracetamol] {i.e. pills}) and the three-drug combination plus Sativex (i.e. 'pills and oral spray'). Information on efficacy and adverse effects was taken from trial data; wording was guided by a panel of neurologists and tested for clarity on lay people. The instrument was administered to 500 participants from Canada's general population using the bidding game approach. Descriptive statistics were calculated. Abstract: ResultsResults Mean (SD) age of participants was 39 (13) years, with a female : male distribution of 56 : 44. The decision board was presented in both English (85%) and French (15%). Of 500 interviewees, 253 (50.6%) chose the 'pills and oral spray'. Mean monthly WTP for the insurance premium for those who chose the 'pills and oral spray' was $Can8 (SD ± 15, median 4, range 0-200). Abstract: ConclusionsConclusions Assuming that 51% of the general population are willing to pay additional premiums as reported in this study, the premiums collected would cover the cost of Sativex for all Canadian MS patients experiencing pain, with a surplus.