Search

Background: Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as approximately half of the patients do not respond adequately to TNFi. Thus, an unmet need exists to better predict therapeutic outcome of biologicals. Objectives: We investigated whether brain activity associated with arthritis measured by functional magnetic resonance imaging (fMRI) of the brain can serve as a predictor of response to TNFi in RA patients. Methods: PreCePRA is a multi-center, randomized, double-blind, placebo-controlled fMRI trial on patients with RA [1] [2]. Active RA patients failing csDMARDs therapy with a DAS28 > 3.2 and at least three tender and/or swollen joints underwent a brain BOLD (blood-oxygen-level dependent) fMRI scan upon joint compression at screening. Patients were then randomized into a 12-week double-blinded treatment phase with 200 mg Certolizumab Pegol (CZP) every two weeks (arm 1: fMRI BOLD signal activated volume > 2000 voxel, i.e. 2 cm3; arm 2: fMRI BOLD signal activated volume

Background: Real time location systems (RTLS) are increasingly used in healthcare with applications that include contract tracing and staffing. However, their potential to provide organizational insights requires staff compliance with the system., Materials and Methods: Our goal is to assess how many nurses are using the RTLS correctly (i.e. complying to the system). We collect RTLS data on the movements of nurses at the Royal Wolverhampton NHS Trust. We identify the number of RTLS active nurses and compare it to what expected from the nurses' rotas., Results: We find that a significant number of nurses appear not to be active from the RTLS data. For approximately 15% of the active users, RTLS records below 10 movements per day. Nevertheless, most of the active users have daily RTLS times consistent with the average shift length., Conclusion: Applications of RTLS data may need to account for imperfect compliance of staff to the system., Competing Interests: Declaration of Competing Interests The authors have no conflicts of interest to disclose. All authors have no financial interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: To examine the prevalence and characteristics of influenza-like illness (ILI) related presentations among people experiencing homelessness compared to the general population as well as to use the Susceptible, Infected, Recovered (SIR) simulation model parameters β and γ to model infectious interactivity, recovery rate, and population-level basic reproduction number (R 0 )., Methods: Using administrative health data from emergency department (ED) visits in the province of Ontario, Canada from 2010 to 2017, an SIR model was used to calculate the R 0 for ILI in both the general population and the population of homeless individuals., Results: From 2010 to 2017, a total of 17,056 homeless and 85,553 non-homeless individuals presented with an ILI to an ED in Ontario. The estimated infectious interactivity (β) was lower while the recovery rate (γ) was longer for infected people experiencing homelessness., Conclusions: Our results suggest that infections of ILI will result in more secondary cases in the homeless population compared to the homed population. This evaluation of the dynamics of ILI spread in the homeless population provides insight into how illnesses such as COVID-19 may be much more infectious in this population compared to the homed population., Competing Interests: Declaration of Competing Interests The authors have no conflicts of interest to disclose. All authors have no financial interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Depression is a common disease influencing patients' quality of life, whose etiology involves complex interactions of environmental, genetic and immunological factors. The latter factors include proinflammatory activation of monocytes and macrophages and increased serum levels of proinflammatory cytokines, altogether formulated as the "macrophage theory of depression". Our current review summarizes the impact of the most commonly used antidepressant drugs on the immune response with special emphasis on the role of macrophages in the clinically observed effects. The anti-inflammatory action of antidepressants mainly results from their direct interaction with immune cells and from changes in the concentration and the relations of neurotransmitters sensed by these cells. The summarized data revealed that Mφs are one of the leading cell populations involved in drug-mediated immune effects that can be observed both in subjects with depression as well as in individuals not suffering from depression. Thus, currently reviewed immunomodulatory effects of the experimental use of different antidepressant drugs suggest the possibility of utilizing them in complex therapeutic strategies dedicated to various inflammatory and immune-mediated diseases. It is worth noting that an excessive inflammatory reaction is also associated with the pathogenesis of various cardiovascular, metabolic and neuro-endocrine diseases. Thus, the inclusion of antidepressants in the complex therapy of these disorders may have beneficial effects through the enhancement of the mood of the patient and alleviation of chronic inflammation. On the other hand, presented data suggest that the influence of chronically used antidepressants on anti-microbial and anti-tumor immunity could also be taken into consideration., (Copyright © 2016 Elsevier GmbH. All rights reserved.)

Classic histology still represents the gold standard in tumor tissue analytics. However, two-dimensional analysis of single tissue slides does not provide a representative overview of the inhomogeneous tumor physiology, and a detailed analysis of complex three-dimensional structures is not feasible with this technique. To overcome this problem, we applied multispectral fluorescence ultramicroscopy (UM) to the field of tumor analysis. Optical sectioning of cleared tumor specimen provides the possibility to three-dimensionally acquire relevant tumor parameters on a cellular resolution. To analyze the virtual UM tumor data sets, we created a novel set of algorithms enabling the fully automatic segmentation and quantification of multiple tumor parameters. This new postmortem imaging technique was applied to determine the therapeutic treatment effect of bevacizumab on the vessel architecture of orthotopic KPL-4 breast cancer xenografts at different time points. A significant reduction of the vessel volume, number of vessel segments, and branching points in the tumor periphery was already detectable 1 day after initiation of treatment. These parameters remained virtually unchanged in the center of the tumor. Furthermore, bevacizumab-induced vessel normalization and reduction in vascular permeability diminished the penetration behavior of trastuzumab-Alexa 750 into tumor tissue. Our results demonstrated that this newimaging method enables the three-dimensional visualization and fully automatic quantification of multiple tumor parameters and drug penetration on a cellular level. Therefore,UM is a valuable tool for cancer research and drug development. It bridges the gap between common macroscopic and microscopic imaging modalities and opens up new three-dimensional (3D) insights in tumor biology.

The autoimmune form of atypical hemolytic uremic syndrome (HUS) is characterized by circulating autoantibodies against the complement regulator factor H, and is often associated with deficiency of the factor H-related proteins CFHR1 and CFHR3. Here we studied whether anti-factor H autoantibodies crossreact with CFHR1, and determined functional consequences of this. In ELISA, anti-factor H immunoglobulin G (IgG) autoantibodies from 24 atypical HUS patients bound to the short consensus repeat 20 domain of factor H, 21 antibodies also recognized CFHR1, but none CFHR3. Three patients also had anti-factor H IgA autoantibodies crossreacting with CFHR1. Analysis of the IgG fractions in CFHR1-deficient patients found that CFHR1-IgG complexes were formed during plasma exchange treatment, indicating that autoantibodies recognize CFHR1 in vivo. Recombinant CFHR1 prevented hemolysis of sheep erythrocytes caused by patient plasma containing anti-factor H IgG, but it did not inhibit red cell lysis caused by a factor H mutation (W1183 L) in the short consensus repeat 20 domain. Thus, exogenous CFHR1 provided during plasma exchange therapy may neutralize anti-factor H autoantibodies and help in the treatment of autoimmune atypical HUS.

The World Health Organisation and other food safety authorities recognise food allergy as a significant public health concern due to the high prevalence and potential severity of the condition and the impact it has on the quality of life and economy. A public health perspective focuses on risk management at the societal level rather than precautions taken by individuals. Allergen lists were originally drawn up on the basis of a combination of prevalence and severity information, but data to document inclusion were limited. Since then the number of allergenic foods for which reactions have been well documented has grown considerably. Yet, most of them are of limited significance to public health. To address food allergy issues from the point of view of risk management, an expert group appointed by the Food Allergy Task Force of the International Life Sciences Institute ILSI Europe reviewed the criteria. We propose a revised set of criteria together with a framework which can be used to help decide which allergenic foods are of sufficient public health importance to be included in allergen lists. Criteria include clinical issues (diagnosis, potency of allergen, severity of reactions), population elements (prevalence, exposure) and modulating factors (food processing). In the framework, data providing evidence for these criteria are weighted according to quality, using a ranking derived from evidence-based medicine. The advantage of this approach is that it makes explicit each of the considerations, thereby rendering the whole process more transparent for all stakeholders.

Atypical hemolytic uremic syndrome (aHUS) is a severe renal disease that is associated with defective complement regulation caused by multiple factors. We previously described the deficiency of factor H-related proteins CFHR1 and CFHR3 as predisposing factor for aHUS. Here we identify in an extended cohort of 147 aHUS patients that 16 juvenile individuals (ie, 11%) who either lacked the CFHR1/CFHR3 completely (n = 14) or showed extremely low CFHR1/CFHR3 plasma levels (n = 2) are positive for factor H (CFH) autoantibodies. The binding epitopes of all 16 analyzed autoantibodies were localized to the C-terminal recognition region of factor H, which represents a hot spot for aHUS mutations. Thus we define a novel subgroup of aHUS, termed DEAP HUS (deficiency of CFHR proteins and CFH autoantibody positive) that is characterized by a combination of genetic and acquired factors. Screening for both factors is obviously relevant for HUS patients as reduction of CFH autoantibody levels represents a therapeutic option.

The atypical form of the kidney disease hemolytic uremic syndrome (aHUS) is associated with defective complement regulation. In addition to mutations in complement regulators, factor H (FH)-specific autoantibodies have been reported for aHUS patients. The aim of the present study was to understand the role of these autoantibodies in aHUS. First, the binding sites of FH autoantibodies from 5 unrelated aHUS patients were mapped using recombinant FH fragments and competitor antibodies. For all 5 autoantibodies, the binding site was localized to the FH C-terminus. In a functional assay, isolated patient IgG inhibited FH binding to C3b. In addition, autoantibody-positive patients' plasma caused enhanced hemolysis of sheep erythrocytes, which was reversed by adding FH in excess. These results suggest that aHUS-associated FH autoantibodies mimic the effect of C-terminal FH mutations, as they inhibit the regulatory function of FH at cell surfaces by blocking its C-terminal recognition region.

Heterozygous mutations in neutrophil elastase have been detected in many sporadic cases of congenital neutropenia. However, a convincing pathogenetic mechanism has not been established, and it is unclear whether the effects of the mutant enzyme occur within the cell of production or are paracrine in nature. The healthy father of a patient was demonstrated to be mosaic for his daughter's Cys42Arg elastase mutation. Using semiquantitative polymerase chain reaction, approximately half of his T cells were shown to carry the mutation in contrast to less than 10% of neutrophils. Individual hematopoietic colonies grown from peripheral blood were heterozygous for the mutation or were homozygous wild type. These results demonstrate that precursors containing the mutation are selectively lost during myelopoiesis or fail to develop into neutrophils. This is the first in vivo confirmation of the pathogenic nature of elastase mutations in humans. The normal neutrophil count in the father suggests that the mutant elastase does not have paracrine effects.

Recurrent bacterial infections, lymphadenopathy, and failure to thrive are unlikely to be attributed to immune deficiency if they occur in the presence of hypergammaglobulinaemia, and other explanations will usually be sought. We describe eight patients who presented with all these features in infancy or early childhood. Deficiencies of immunoglobulin and antibody production were initially discounted, and the children were referred for investigation of possible lymphoma, autoimmune disease, or chronic viral infection. The patients were later referred to us for more detailed immunological investigation, which revealed low levels of IgG2 and poor specific antibody production to common pathogens. Treatment with intravenous immunoglobulin resulted in resolution of signs and symptoms in all patients. Thus we have shown that hypergammaglobulinaemia does not preclude the presence of immunoglobulin/antibody deficiency. We suggest that investigation of children with high levels of IgG and features of immunodeficiency should include IgG subclass analysis.

An inexpensive animal model is described, for investigation of the immunogenicity of substances such as food additives. Inbred mice were immunised with antigen emulsified in complete Freund's adjuvant, and specific cell-mediated immunity subsequently measured by a footpad swelling test. This method has been applied in an investigation of the immunogenicity of the exudate gums, gum arabic, gum karaya and gum tragacanth. These substances are capable of eliciting an immune response which is comparable to the specific immune responses elicited by a protein antigen, e.g. hens' egg ovalbumin. Purification of commercially available gum preparations led to a significant (P less than 0.005) reduction of the immune response under in vivo test conditions.

Triticone A is one member of a family of novel compounds which are spirocyclic lactams produced by several plant pathogenic fungi including Drechslera tritici repentis on wheat. It undergoes racemization to form triticone B and when tested, the enantiomeric mixture causes chlorosis and necrosis on a wide range of plants. Fluorescein diacetate treated protoplasts in conjunction with various triticone treatments allowed for accurate quantitation of the biological activity of the toxin. Various physiological functions of the wheat cell are impaired including the Hill and CO2 fixation reactions in photosynthesis. In addition, triticone A inhibits enzymes that have SH functional groups as part of their active site, eg., the protease-ficin. Neither triticone C or D had any activity in the enzyme or protoplast assays. It is apparent that triticone A has some potential as a molecular probe in a variety of biological systems.