Objective
The nuclear oncoprotein DEK is an autoantigen associated with juvenile idiopathic arthritis (JIA), especially the oligoarticular subtype. DEK is a secreted chemotactic factor. Abundant ...levels of DEK and DEK autoantibodies are found in inflamed synovium in JIA. We undertook this study to further characterize the nature of DEK autoantibodies in screening serum samples from 2 different cohorts that consisted mostly of patients with JIA.
Methods
DEK autoantibody levels were analyzed in sera from 33 JIA patients, 13 patients with other inflammatory conditions, and 11 healthy controls, as well as in 89 serum samples from JIA patients receiving anti–tumor necrosis factor (anti‐TNF) therapy. Recombinant His‐tagged full‐length DEK protein (1–375 amino acids aa) and the 187–375‐aa and 1–350‐aa His‐tagged DEK fragments made in a baculovirus system were used for enzyme‐linked immunosorbent assay (ELISA) and immunoblotting. The C‐terminal 25‐aa fragment of DEK was expressed in a glutathione S‐transferase–tagged vector. ELISA results were calculated as area under the curve by the trapezoidal rule.
Results
DEK autoantibody levels were significantly higher in patients with polyarticular JIA than in those with oligoarticular JIA, and were higher in patients with polyarticular JIA who had more active disease after cessation of anti‐TNF therapy. Immunoblotting against the C‐terminal 25‐aa fragment of DEK confirmed that this section of the DEK molecule is the most immunogenic domain.
Conclusion
DEK autoantibody levels are higher in patients with polyarticular JIA than in those with oligoarticular JIA, and higher in patients who have disease flares after cessation of anti‐TNF therapy. The C‐terminal 25‐aa fragment is the most immunogenic portion of DEK. These findings are significant with respect to the nature of DEK autoantibodies, their contribution to JIA pathogenesis, and their implications for JIA management.
Chronic granulomatous disease (CGD) is a rare inherited immunodeficiency syndrome that results from abnormal nicotinamide adenine dinucleotide phosphate (NADPH) oxidase function. This defect leads to ...recurrent catalase-positive bacterial and fungal infections as well as associated granuloma formation. We review the case of a 2-year-old boy who presented with ascites and fever of an unknown origin as manifestations of CGD. Cultures were negative for infection throughout his course, and CGD was suspected after identification of granulomas on peritoneal biopsy. Genetic testing revealed a novel mutation in the CYBB gene underlying his condition. This paper highlights the importance of considering CGD in the differential diagnosis of fever of unknown origin and ascites in children.
Biologics treatment with antitumour necrosis factor alpha (TNFα) is efficacious in patients with juvenile idiopathic arthritis (JIA). Despite displaying clinical inactivity during treatment, many ...patients will flare on cessation of therapy. The inability to definitively discriminate patients who will relapse or continue to remain in remission after therapy withdrawal is currently a major unmet medical need. CD4 T cells have been implicated in active disease, yet how they contribute to disease persistence despite treatment is unknown.
We interrogated the circulatory reservoir of CD4
immune subsets at the single-cell resolution with mass cytometry (cytometry by time of flight) of patients with JIA (n=20) who displayed continuous clinical inactivity for at least 6 months with anti-TNFα and were subsequently withdrawn from therapy for 8 months, and scored as relapse or remission. These patients were examined prior to therapy withdrawal for putative subsets that could discriminate relapse from remission. We verified on a separate JIA cohort (n=16) the dysregulation of these circulatory subsets 8 months into therapy withdrawal. The immunological transcriptomic signature of CD4 memory in relapse/remission patients was examined with NanoString.
An inflammatory memory subset of CD3
CD4
CD45RA
TNFα
T cells deficient in immune checkpoints (PD1
CD152
) was present in relapse patients prior to therapy withdrawal. Transcriptomic profiling reveals divergence between relapse and remission patients in disease-centric pathways involving (1) T-cell receptor activation, (2) apoptosis, (3) TNFα, (4) nuclear factor-kappa B and (5) mitogen-activated protein kinase signalling.
A unique discriminatory immunomic and transcriptomic signature is associated with relapse patients and may explain how relapse occurs.
The financial support by the EPSRC for studentship funding (SSC) through the M3S Doctoral Training Centre (Grant EP/L015862/1) and Altro Ltd. The impact of emergent pathogens Since the 1970s, more ...than 1,500 new pathogens have been discovered, and many of these have had major impacts on public health 1. ...MDR pathogens are now considered a global threat to public health 3,4. ...even after cleaning, there remains a risk of transmission particularly for pathogens with a low infective dose. Persistence of viral pathogens on common dry inanimate surfaces (e.g., plastics, stainless steel, or flooring). https://doi.org/10.1371/journal.ppat.1008880.t002 There are two broadly different, but not mutually exclusive, strategies used in developing antimicrobial surfaces: biocidal surfaces that kill microbes, and anti-biofouling surfaces that reduce microbial adhesion and prevent subsequent biofilm formation (Fig 1).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, delayed hypersensitivity reaction (DHR). We observed DRESS to inhibitors of interleukin 1 (IL-1) or IL-6 in a small group of ...patients with Still's disease with atypical lung disease. We sought to characterise features of patients with Still's disease with DRESS compared with drug-tolerant Still's controls. We analysed human leucocyte antigen (HLA) alleles for association to inhibitor-related DHR, including in a small Kawasaki disease (KD) cohort.
In a case/control study, we collected a multicentre series of patients with Still's disease with features of inhibitor-related DRESS (n=66) and drug-tolerant Still's controls (n=65). We retrospectively analysed clinical data from all Still's subjects and typed 94/131 for HLA. European Still's-DRESS cases were ancestry matched to International Childhood Arthritis Genetics Consortium paediatric Still's cases (n=550) and compared for HLA allele frequencies. HLA association also was analysed using Still's-DRESS cases (n=64) compared with drug-tolerant Still's controls (n=30). KD subjects (n=19) were similarly studied.
Still's-DRESS features included eosinophilia (89%), AST-ALT elevation (75%) and non-evanescent rash (95%; 88% involving face). Macrophage activation syndrome during treatment was frequent in Still's-DRESS (64%) versus drug-tolerant Still's (3%; p=1.2×10
). We found striking enrichment for HLA-DRB1*15 haplotypes in Still's-DRESS cases versus INCHARGE Still's controls (p=7.5×10
) and versus self-identified, ancestry-matched Still's controls (p=6.3×10
). In the KD cohort, DRB1*15:01 was present only in those with suspected anakinra reactions.
DRESS-type reactions occur among patients treated with IL-1/IL-6 inhibitors and strongly associate with common HLA-DRB1*15 haplotypes. Consideration of preprescription HLA typing and vigilance for serious reactions to these drugs are warranted.
Abstract BACKGROUND Posterior fossa syndrome (PFS) is a constellation of neurobehavioral symptoms occurring in 8–24% of children following surgical resection of posterior fossa tumors. Symptoms may ...include a combination of mutism or reduced verbal output, emotional lability, hypotonia, dysphagia, ataxia and weakness. Direct surgical injury to the dentato-thalamo-cortical pathway has been the proposed pathological mechanism. The trajectory of recovery and the functional outcomes of PFS are not well described. Khan et al. published a prospective study on children after medulloblastoma resection where they divided PFS into type 1 (complete mutism) and type 2 (diminished speech). They showed that PFS type 1 patients had a worse prognosis and a delayed recovery with 44.4% of children being non-ambulatory at one year. Ricci et al. recently published a more detailed severity grading algorithm which over time will hopefully help with data collection and analysis leading to improved prognostication regarding functional recovery. METHODS We present a unique longitudinal look (range 12 months to 19 years) at 5 pediatric patients with posterior fossa tumors who developed PFS following their tumor resections. RESULTS Tumor diagnoses included ependymoma and medulloblastoma. Rehabilitation interventions consisted of acute inpatient rehabilitation where they received intensive physical, occupational, speech and feeding therapy. Most patients benefited from early utilization of trunk and lower extremity bracing as well as a variety of assistive devices and durable medical equipment. Patients continued their rehabilitation for months to years in an outpatient and school setting. All patients demonstrated significant neurological and functional gains however, none of them had a complete resolution of symptoms. We discuss the anatomy, the time to symptom onset, the trajectory of our patients’ recoveries and the rationale behind the applied rehabilitation strategies. CONCLUSIONS This work gives insights on long term sequalae of PFS and demonstrates current rehabilitation approach for children with this complex condition.
Use of selective serotonin reuptake inhibitors (SSRIs) is common during pregnancy. Fetal exposure to SSRIs is associated with persistent pulmonary hypertension of the newborn (PPHN); however, a ...direct link between the two has yet to be established. Conversely, it is well known that PPHN can be caused by premature constriction of the ductus arteriosus (DA), a fetal vessel connecting the pulmonary and systemic circulations. We hypothesized that SSRIs could induce in utero DA constriction. Using isolated vessels and whole-animal models, we sought to determine the effects of two commonly prescribed SSRIs, fluoxetine and sertraline, on the fetal mouse DA. Cannulated vessel myography studies demonstrated that SSRIs caused concentration-dependent DA constriction and made vessels less sensitive to prostaglandin-induced dilation. Moreover, in vivo studies showed that SSRI-exposed mice had inappropriate DA constriction in utero. Taken together, these findings establish that SSRIs promote fetal DA constriction and provide a potential mechanism by which SSRIs could contribute to PPHN.
Abstract
California faces crisis conditions on its forested landscapes. A century of aggressive logging and fire suppression in combination with conditions exacerbated by climate change have created ...an ongoing ecological, economic, and public health emergency. Between commercial harvests on California’s working forestlands and the increasing number of acres the state treats each year for fire risk reduction and carbon sequestration, California forests generate millions of tons of woody residues annually—residues that are typically left or burned in the field. State policymakers have turned to biomass electricity generation as a key market for woody biomass in the hope that it can support sustainable forest management activities while also providing low-carbon renewable electricity. However, open questions surrounding the climate and air pollution performance of electricity generation from woody biomass have made it difficult to determine how best to manage the risks and opportunities posed by forest residues. The California Biomass Residue Emissions Characterization (C-BREC) model offers a spatially-explicit life cycle assessment framework to rigorously and transparently establish the climate and air pollution impacts of biopower from forest residues in California under current conditions. The C-BREC model characterizes the variable emissions from different biomass supply chains as well as the counterfactual emissions from prescribed burn, wildfire, and decay avoided by residue mobilization. We find that the life cycle ‘carbon footprint’ of biopower from woody residues generated by recent forest treatments in California ranges widely—from comparable with solar photovoltaic on the low end to comparable with natural gas on the high end. This variation stems largely from the heterogeneity in the fire and decay conditions these residues would encounter if left in the field, with utilization of residue that would otherwise have been burned in place offering the best climate and air quality performance. California’s energy and forest management policies should account for this variation to ensure desired climate benefits are achieved.
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