Search

Objectives: Symptoms of insomnia are highly prevalent in the elderly. A significant number of pharmacological and non‐pharmacological interventions exist, but, up‐to‐date, their comparative efficacy and safety has not been sufficiently assessed. Methods: We integrated the randomized evidence from every available treatment for insomnia in the elderly (>65 years) by performing a network meta‐analysis. Several electronic databases were searched up to May 25, 2019. The two primary outcomes were total sleep time and sleep quality. Data for other 6 efficacy and 8 safety outcomes were also analyzed. Results: Fifty‐three RCTs with 6832 participants (75 years old on average) were included, 43 of which examined the efficacy of one or more drugs. Ten RCTs examined the efficacy of non‐pharmacological interventions and were evaluated only with pairwise meta‐analyses because they were disconnected from the network. The overall confidence in the evidence was very low primarily due to the small amount of data per comparison and their sparse connectedness. Several benzodiazepines, antidepressants, and z‐drugs performed better in both primary outcomes, but few comparisons had data from more than one trial. The limited evidence on non‐pharmacological interventions suggested that acupressure, auricular acupuncture, mindfulness‐based stress reduction program, and tart cherry juice were better than their control interventions. Regarding safety, no clear differences were detected among interventions due to large uncertainty. Conclusions: Insufficient evidence exists on which intervention is more efficacious for elderly patients with insomnia. More RCTs, with longer duration, making more direct interventions among active treatments and presenting more outcomes are urgently needed. [ABSTRACT FROM AUTHOR]

In this Letter, the authors present the experimental verification of an analytical model, which captures the realistic shape of bond wire antennas (BWAs) in dependence on the wire bonding and design parameters. Using the verified model, the impact of the shape of the wires on the performance of BWAs is quantified. [ABSTRACT FROM AUTHOR]

In this study a stochastic approach, based on several simplifying assumptions, is developed that allows an estimation of the effects of nonregular spatial patterns of the distribution of individual plants on yield per area. In this approach, two random variables were attached to each individual plant: single plant yield and individual space per plant. The latter can be estimated, for example, by the area of Thiessen polygons. Yield per area is calculated theoretically by the expectation ( = mean) of the ratio between individual yield and area. Based on the logarithmic relationship between single plant yield and individual space per plant, yield per area can be broken down into three additive terms:the first term depends only on the mean of individual plant areas, while the second depends on their mean and variance simultaneously. This second term is the product of the variance and a factor which depends only on the mean. The third term is a function of the mean and of higher order (≥ 3) central moments of a fractional linear transformation of individual plant area. Finally, these theoretical concepts were applied to 17 experimental data sets of three cultivars of winter oilseed rape (Brassica napus L.) with measurements for single plant yields and individual areas for the Thiessen polygon tesselations. Since yield per area is theoretically defined by the expectation of the ratio between individual yield and area, it is estimated by the arithmetic mean of the individual yield/area-ratios. The agreement between this estimate and the sum of the estimated terms from the aforementioned additive decomposition of yield per area is particularly good. For the 17 data sets, percentages for these additive terms of approximately 71.4 % up to 98.4 % (mean: 89.0 %) for the first term, 1.6 % up to 20.0 % (mean: 9.8 %) for the second term and 0 % up to 8.7 % (mean: 1.2 %) for the third term are obtained. As a consequence it may be concluded, that yield per area can be... [ABSTRACT FROM AUTHOR]

Demonstrates the highly efficient compatible-solute-assisted periplasmic production of recombinant chimeric molecules. Use of protein-stabilizing compatible solutes during the production phase and/or in the course of purification and storage; Standard method of producing recombinant proteins such as immunotoxins in large quantities.

Caused by nonperfect seed placement accuracy of sowing machines as well as by many other abiotic and biotic factors the resulting plant stands exhibit nonregular plant distributions. Based on several simplifying assumptions a stochastic approach provides a quantitative determination of the effects of accuracy of sowing technique on yield per area. In this approach, two random variables are assigned to each individual plant: single plant yield E and single plant area A, which is calculated in this paper by the construction and quadrature of the so-called Thiessen-polygons. The yield per area F is calculated as the expectation of the ratio E/A. By assuming a deterministic mathematical relationship between E and A, the calculation of F reduces to the calculation of the expectation of a function of only one random variable A. A simple approximation with sufficient accuracy for many applications only depends on the mean and on the variance of the areas of the individual plants. For demonstration purposes, the theoretical approaches and results have been finally applied to three data sets for drilled seeds of winter oilseed rape (plant density: 60 plants/m² and distance between rows: 10 cm). These data sets exhibit different accuracies of the longitudinal distributions within rows which have been quantitatively measured by the coefficient of variation for the distances between plants within rows: Yield depression increases with an increasing variability of plant distances within rows. [ABSTRACT FROM AUTHOR]

Investigates the electrochemical oxidation of (NiII(eta5-C5Ph5)(Ph2PCH=C(O)Ph)) and (NiII(eta5-C5Ph5)(Ph2PCH=C(O)Fc)) in dichloromethane. Rotating disk and cyclic voltammetry; Thin-layer spectroelectrochemistry and electron paramagnetic resonance (EPR) spectroscopy.

In this Letter, the authors present the experimental verification of an analytical model, which captures the realistic shape of bond wire antennas (BWAs) in dependence on the wire bonding and design parameters. Using the verified model, the impact of the shape of the wires on the performance of BWAs is quantified. [ABSTRACT FROM AUTHOR]

Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumor in children and is highly resistant to all forms of treatment currently available once metastasis or relapse has commenced. As it has recently been determined that the acetylcholine receptor (AChR) ?-subunit, which defines the fetal AChR (fAChR) isoform, is almost exclusively expressed in RMS post partum, we recombinantly fused a single chain variable fragment (scFv) derived from a fully human anti-fAChR Fab-fragment to Pseudomonas exotoxin A to generate an anti-fAChR immunotoxin (scFv35-ETA).While scFv35-ETA had no damaging effect on fAChR-negative control cell lines, it killed human embryonic and alveolar RMS cell lines in vitro and delayed RMS development in a murine transplantation model. These results indicate that scFv35-ETA may be a valuable new therapeutic tool as well as a relevant step towards the development of a fully human immunotoxin directed against RMS. Moreover, as approximately 20% of metastatic malignant melanomas (MMs) display rhabdoid features including the expression of fAChR, the immunotoxin we developed may also prove to be of significant use in the treatment of these more common and most often fatal neoplasms. [ABSTRACT FROM AUTHOR]

Background:Antibody drug conjugates (ADCs) and immunotoxins (ITs) are promising anticancer immunotherapeutics. Despite their encouraging performance in clinical trials, both ADCs and ITs often suffer from disadvantages such as stoichiometrically undefined chemical linkage of the cytotoxic payload (ADCs) and the potential immunogenicity of toxins derived from bacteria and plants (ITs).Methods:Human microtubule-associated protein tau (MAP) was cloned in-frame with human EGF, expressed in E. coli and purified by standard chromatographic methods. The in vitro activity was confirmed by flow cytometry, cell viability assays and tubulin polymerisation assay. The in vivo efficacy was demonstrated using noninvasive far-red in vivo imaging.Results:The EGF-MAP selectively induced apoptosis in EGFR-overexpressing proliferating cancer cells through stabilisation of microtubules. Nonproliferating cells were not affected, demonstrating superior selectivity of EGF-MAP for cancer cells. The EGF-MAP was well tolerated at high doses in mice compared with the ETA'-based control. The in vivo efficacy of EGF-MAP was demonstrated in a tumour xenograft mouse model.Conclusion:Our data indicate the general mechanism of action for a new class of human immunotherapeutic reagents suitable for the treatment of cancer. This approach combines the binding specificity of targeting ligands with the selective cytotoxicity of MAP towards proliferating cells. [ABSTRACT FROM AUTHOR]

Background Dysregulated, activated macrophages play a pivotal role in chronic inflammatory diseases such as arthritis and atopic dermatitis. These cells display increased expression of the high-affinity Fcγ receptor (CD64), making them ideal targets for CD64-specific immunotoxins. We previously showed that a chemically linked immunotoxin, the monoclonal H22-RicinA, specifically eliminated infiltrating activated macrophages and resolved chronic cutaneous inflammation. However, several disadvantages are associated with classic immunotoxins, and we therefore followed a fusion protein strategy to express the antigen-binding site alone (scFv H22) fused to a derivative of Pseudomonas exotoxin A (ETA′). Objectives To assess the potential effect of increased valency on efficacy, we produced monovalent [H22(scFv)-ETA′] and bivalent [H22(scFv)2-ETA′] versions and evaluated their potential for eliminating activated macrophages both in vitro and in vivo. Methods Both immunotoxins were produced by bacterial fermentation. Binding was assessed by flow cytometry on the monocytic CD64+ cell line U937. Toxicity was analysed by XTT and apoptosis induction by annexin V bioassay. The in vivo effect was tested in a human CD64 transgenic mouse model for cutaneous inflammation. Results The cytotoxic effects of both immunotoxins were clearly due to apoptosis with an IC50 of 140 pmol L−1 for monovalent and only 14 pmol L−1 for the divalent version. In vivo treatment with H22(scFv)-ETA′ reduced CD64+ activated macrophages to 21% of their initial numbers whereas H22(scFv)2-ETA′ treatment reduced these cells to 4·8% ( P < 0·001). Conclusions These data clearly show increased efficacy due to increased valency of the anti-CD64 immunotoxin. Both recombinant immunotoxins have a low IC50, making them suitable for the treatment of diseases involving dysregulated, activated macrophages. [ABSTRACT FROM AUTHOR]

Background Specific immunotherapy is the only curative therapy for type I allergies and the alarming increase in allergy prevalence emphasizes the need for additional/alternative strategies for curative treatment. Allergen toxins (AT), fusion products of an allergen with an apoptosis inducing cytotoxin, are a new kind of immunotoxin. Objective AT should allow allergen-specific targeting and elimination of allergy-relevant cells, with B cells being the primary target. An important question is the fate of the effector cells, e.g. mast cells and basophils, which carry allergen-specific IgE: the immunotoxin might even prove to be harmful. Methods We established a reliable in vitro B cell model (using two mouse hybridoma cell lines) for testing specificity and toxicity of P5-ETA′, a fusion protein of the major timothy grass pollen allergen Phl p 5b and truncated Pseudomonas Exotoxin A. In a second step, we investigated the impact of the AT on human basophils. Results P5-ETA′ reliably eliminated Phl p 5-specific cells in the in vitro B cell model, leaving unspecific B cells unharmed. Human basophils of grass pollen allergic donors specifically bound P5-ETA′, released IL-4 and up-regulated the activation marker CD203c, but were not subject to the toxic effect because of lack of internalization of IgE-bound allergen. Conclusion According to our data, basophils are pure effector cells in the context of IgE-bound allergen and not involved in classical antigen presentation. [ABSTRACT FROM AUTHOR]