Nonsense mutations in alpha-II spectrin in three families with juvenile onset hereditary motor neuropathy

Distal hereditary motor neuropathies are a rare subgroup of inherited peripheral neuropathies hallmarked by a length-dependent axonal degeneration of lower motor neurons without significant involvement of sensory neurons. We identified patients with heterozygous nonsense mutations in the alpha II-spectrin gene, SPTAN1, in three separate dominant hereditary motor neuropathy families via next-generation sequencing. Variable penetrance was noted for these mutations in two of three families, and phenotype severity differs greatly between patients. The mutant mRNA containing nonsense mutations is broken down by nonsense-mediated decay and leads to reduced protein levels in patient cells. Previously, dominant-negative alpha II-spectrin gene mutations were described as causal in a spectrum of epilepsy phenotypes

Organic contaminants in bio-based fertilizer treated soil:Target and suspect screening approaches

Using bio-based fertilizer (BBF) in agricultural soil can reduce the dependency on chemical fertilizer and increase sustainability by recycling nutrient-rich side-streams. However, organic contaminants in BBFs may lead to residues in the treated soil. This study assessed the presence of organic contaminants in BBF treated soils, which is essential for evaluating sustainability/risks of BBF use. Soil samples from two field studies amended with 15 BBFs from various sources (agricultural, poultry, veterinary, and sludge) were analyzed. A combination of QuEChERS-based extraction, liquid chromatography quadrupole time of flight mass spectrometry-based (LC-QTOF-MS) quantitative analysis, and an advanced, automated data interpretation workflow was optimized to extract and analyze organic contaminants in BBF-treated agricultural soil. The comprehensive screening of organic contaminants was performed using target analysis and suspect screening. Of the 35 target contaminants, only three contaminants were detected in the BBF-treated soil with concentrations ranging from 0.4 ng g -1 to 28.7 ng g -1; out of these three detected contaminants, two were also present in the control soil sample. Suspect screening using patRoon (an R-based open-source software platform) workflows and the NORMAN Priority List resulted in tentative identification of 20 compounds (at level 2 and level 3 confidence level), primarily pharmaceuticals and industrial chemicals, with only one overlapping compound in two experimental sites. The contamination profiles of the soil treated with BBFs sourced from veterinary and sludge were similar, with common pharmaceutical features identified. The suspect screening results suggest that the contaminants found in BBF-treated soil might come from alternative sources other than BBFs

Concepts and characteristics of the 'COST Reference Microplasma Jet'

Biomedical applications of non-equilibrium atmospheric pressure plasmas have attracted intense interest in the past few years. Many plasma sources of diverse design have been proposed for these applications, but the relationship between source characteristics and application performance is not well-understood, and indeed many sources are poorly characterized. This circumstance is an impediment to progress in application development. A reference source with well-understood and highly reproducible characteristics may be an important tool in this context. Researchers around the world should be able to compare the characteristics of their own sources and also their results with this device. In this paper, we describe such a reference source, developed from the simple and robust micro-scaled atmospheric pressure plasma jet (μ-APPJ) concept. This development occurred under the auspices of COST Action MP1101 'Biomedical Applications of Atmospheric Pressure Plasmas'. Gas contamination and power measurement are shown to be major causes of irreproducible results in earlier source designs. These problems are resolved in the reference source by refinement of the mechanical and electrical design and by specifying an operating protocol. These measures are shown to be absolutely necessary for reproducible operation. They include the integration of current and voltage probes into the jet. The usual combination of matching unit and power supply is replaced by an integrated LC power coupling circuit and a 5 W single frequency generator. The design specification and operating protocol for the reference source are being made freely available

Geriatric pharmacotherapy : optimisation through integrated approach in the hospital setting

Since older patients are more vulnerable to adverse drug-related events, there is a need to ensure appropriate prescribing in these patients in order to prevent misuse, overuse and underuse of drugs. Different tools and strategies have been developed to reduce inappropriate prescribing; the available measures can be divided into medication assessment tools, and specific interventions to reduce inappropriate prescribing. Implicit criteria of inappropriate prescribing focus on appropriate dosing, search for drug-drug interactions, and increase adherence. Explicit criteria are consensus-based standards focusing on drugs and diseases and include lists of drugs to avoid in general or lists combining drugs with clinical data. These criteria take into consideration differences between patients, and stand for a medication review, by using a systematic approach. Different types of interventions exist in order to reduce inappropriate prescribing in older patients, such as: educational interventions, computerized decision support systems, pharmacist-based interventions, and geriatric assessment. The effects of these interventions have been studied, sometimes in a multifaceted approach combining different techniques, and all types seem to have positive effects on appropriateness of prescribing. Interdisciplinary teamwork within the integrative pharmaceutical care is important for improving of outcomes and safety of drug therapy. The pharmaceutical care process consists offour steps, which are cyclic for an individual patient. These steps are pharmaceutical anamnesis, medication review, design and follow-up of a pharmaceutical care plan. A standardized approach is necessary for the adequate detection and evaluation of drug-related problems. Furthermore, it is clear that drug therapy should be reviewed in-depth, by having full access to medical records, laboratory values and nursing notes. Although clinical pharmacists perform the pharmaceutical care process to manage the patient’s drug therapy in every day clinical practice, the physician takes the ultimate responsibility for the care of the patient in close collaboration with nurses

Intravenous ATP infusions can be safely administered in the home setting: a study in pre-terminal cancer patients

The aim of the study was to investigate the safety of adenosine 5′-triphosphate (ATP) administration at home in pre-terminal cancer patients. Included were patients with cancer for whom medical treatment options were restricted to supportive care, who had a life expectancy of less than 6 months, a World Health Organization performance status 1 or 2, and suffered from at least one of the following complaints: fatigue, anorexia or weight loss >5% over the previous 6 months. Side effects were registered systematically on a standard form according to the National Cancer Institute (NCI) Common Toxicity Criteria. Fifty-one patients received a total of 266 intravenous ATP infusions. Of these, 11 infusions (4%) were given at the lowest dose of 20 μg kg−1 min−1, 85 infusions (32%) at 25–40 μg kg−1 min−1, and 170 (64%) at the highest dose of 45–50 μg kg−1 min−1 ATP. The majority of ATP infusions (63%) were without side effects. Dyspnea was the most common side effect (14% of infusions), followed by chest discomfort (12%) and the urge to take a deep breath (11%). No symptoms of cardiac ischemia occurred in any of the infusions. All side effects were transient and resolved within minutes after lowering the ATP infusion rate. Side effects were most frequent in the presence of cardiac disorders. We conclude that ATP at a maximum dose of 50 μg kg−1 min−1 can be safely administered in the home setting in patients with pre-terminal cancer

Immune Modulation by Design: Using Topography to Control Human Monocyte Attachment and Macrophage Differentiation

© 2020 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Macrophages play a central role in orchestrating immune responses to foreign materials, which are often responsible for the failure of implanted medical devices. Material topography is known to influence macrophage attachment and phenotype, providing opportunities for the rational design of “immune-instructive” topographies to modulate macrophage function and thus foreign body responses to biomaterials. However, no generalizable understanding of the inter-relationship between topography and cell response exists. A high throughput screening approach is therefore utilized to investigate the relationship between topography and human monocyte–derived macrophage attachment and phenotype, using a diverse library of 2176 micropatterns generated by an algorithm. This reveals that micropillars 5–10µm in diameter play a dominant role in driving macrophage attachment compared to the many other topographies screened, an observation that aligns with studies of the interaction of macrophages with particles. Combining the pillar size with the micropillar density is found to be key in modulation of cell phenotype from pro to anti-inflammatory states. Machine learning is used to successfully build a model that correlates cell attachment and phenotype with a selection of descriptors, illustrating that materials can potentially be designed to modulate inflammatory responses for future applications in the fight against foreign body rejection of medical devices

Induction of broad multifunctional CD8+ and CD4+ T cells by hepatitis B virus antigen-based synthetic long peptides ex vivo

Introduction: Therapeutic vaccination based on synthetic long peptides (SLP®) containing both CD4+ and CD8+ T cell epitopes is a promising treatment strategy for chronic hepatitis B infection (cHBV). Methods: We designed SLPs for three HBV proteins, HBcAg and the non-secreted proteins polymerase and X, and investigated their ability to induce T cell responses ex vivo. A set of 17 SLPs was constructed based on viral protein conservation, functionality, predicted and validated binders for prevalent human leukocyte antigen (HLA) supertypes, validated HLA I epitopes, and chemical producibility. Results: All 17 SLPs were capable of inducing interferon gamma (IFNɣ) production in samples from four or more donors that had resolved an HBV infection in the past (resolver). Further analysis of the best performing SLPs demonstrated activation of both CD8+ and CD4+ multi-functional T cells in one or more resolver and patient sample(s). When investigating which SLP could activate HBV-specific T cells, the responses could be traced back to different peptides for each patient or resolver. Discussion: This indicates that a large population of subjects with different HLA types can be covered by selecting a suitable mix of SLPs for therapeutic vaccine design. In conclusion, we designed a set of SLPs capable of inducing multifunctional CD8+ and CD4+ T cells ex vivo that create important components for a novel therapeutic vaccine to cure cHBV.</p

Improved science-based transformation pathways for the development of safe and sustainable plastics

Environmental Biolog