A standardized human model to study early pathogenic events in patients with psoriasis is missing. Activation of Toll-like receptor 7/8 by means of topical application of imiquimod is the most ...commonly used mouse model of psoriasis.
We sought to investigate the potential of a human imiquimod patch test model to resemble human psoriasis.
Imiquimod (Aldara 5% cream; 3M Pharmaceuticals, St Paul, Minn) was applied twice a week to the backs of volunteers (n = 18), and development of skin lesions was monitored over a period of 4 weeks. Consecutive biopsy specimens were taken for whole-genome expression analysis, histology, and T-cell isolation. Plasmacytoid dendritic cells (pDCs) were isolated from whole blood, stimulated with Toll-like receptor 7 agonist, and analyzed by means of extracellular flux analysis and real-time PCR.
We demonstrate that imiquimod induces a monomorphic and self-limited inflammatory response in healthy subjects, as well as patients with psoriasis or eczema. The clinical and histologic phenotype, as well as the transcriptome, of imiquimod-induced inflammation in human skin resembles acute contact dermatitis rather than psoriasis. Nevertheless, the imiquimod model mimics the hallmarks of psoriasis. In contrast to classical contact dermatitis, in which myeloid dendritic cells sense haptens, pDCs are primary sensors of imiquimod. They respond with production of proinflammatory and TH17-skewing cytokines, resulting in a TH17 immune response with IL-23 as a key driver. In a proof-of-concept setting systemic treatment with ustekinumab diminished imiquimod-induced inflammation.
In human subjects imiquimod induces contact dermatitis with the distinctive feature that pDCs are the primary sensors, leading to an IL-23/TH17 deviation. Despite these shortcomings, the human imiquimod model might be useful to investigate early pathogenic events and prove molecular concepts in patients with psoriasis.
Display omitted
This paper highlights the different options associated with asynchronous online discussion (AOD) use in health care education which may have an impact on their effectiveness. The review was carried ...out following a search of specific databases, websites, key journals, references and key authors. All studies published between 2006 and 2012 that met specific inclusion/exclusion criteria were subject to quality appraisal. Fourteen studies met the quality appraisal criteria: six qualitative, four quasi-experimental, one observational and three mixed methods. Data extraction coupled with narrative synthesis enabled the description of options that emerged and exploration of the relationships within and between studies. Study design as well as methodological quality was mixed. However, several useful factors emerged which may impact on effectiveness. These include (a) the mode of e-moderation (b) provision of AOD for participants in the clinical setting to critically reflect, analyse and resolve clinical issues and (c) increased amount of time spent reading the AOD (but not the number of discussion ‘hits’). Research in this area appears to be in its infancy and one of the main recommendations is that further studies are required which focus on comparing the same type of AOD with and without a specific intervention in order to make any robust conclusions.
•More research needed comparing online discussion with and without an intervention.•Online discussion may help students learn from experience when in clinical practice.•Factors such as group size, length of time and framework used may affect learning.•Factors such as peer moderation and use of clinical scenarios may affect learning.
An important feature of atopic asthma is the T cell-driven late phase reaction involving transient bronchoconstriction followed by development of airways hyperresponsiveness (AHR). Using a unique rat ...asthma model we recently showed that the onset and duration of the aeroallergen-induced airway mucosal T cell activation response in sensitized rats is determined by the kinetics of functional maturation of resident airway mucosal dendritic cells (AMDCs) mediated by cognate interactions with CD4+ T helper memory cells. The study below extends these investigations to chronic aeroallergen exposure. We demonstrate that prevention of ensuing cycles of T cell activation and resultant AHR during chronic exposure of sensitized rats to allergen aerosols is mediated by CD4+CD25+Foxp3+LAG3+ CTLA+CD45RC+ T cells which appear in the airway mucosa and regional lymph nodes within 24 h of initiation of exposure, and inhibit subsequent Th-mediated upregulation of AMDC functions. These cells exhibit potent regulatory T (T reg) cell activity in both in vivo and ex vivo assay systems. The maintenance of protective T reg activity is absolutely dependent on continuing allergen stimulation, as interruption of exposure leads to waning of T reg activity and reemergence of sensitivity to aeroallergen exposure manifesting as AMDC/T cell upregulation and resurgence of T helper 2 cytokine expression, airways eosinophilia, and AHR.
Darier's disease (DD) is a genodermatosis caused by mutations of the ATP2A2 gene leading to disrupted keratinocyte adhesion. Recurrent episodes of skin inflammation and infections with a typical ...malodour in DD indicate a role for microbial dysbiosis. Here, for the first time, we investigated the DD skin microbiome using a metabarcoding approach of 115 skin swabs from 14 patients and 14 healthy volunteers. Furthermore, we analyzed its changes in the context of DD malodour and the cutaneous DD transcriptome.
We identified a disease-specific cutaneous microbiome with a loss of microbial diversity and of potentially beneficial commensals. Expansion of inflammation-associated microbes such as Staphylococcus aureus and Staphylococcus warneri strongly correlated with disease severity. DD dysbiosis was further characterized by abundant species belonging to Corynebacteria, Staphylococci and Streptococci groups displaying strong associations with malodour intensity. Transcriptome analyses showed marked upregulation of epidermal repair, inflammatory and immune defence pathways reflecting epithelial and immune response mechanisms to DD dysbiotic microbiome. In contrast, barrier genes including claudin-4 and cadherin-4 were downregulated.
These findings allow a better understanding of Darier exacerbations, highlighting the role of cutaneous dysbiosis in DD inflammation and associated malodour. Our data also suggest potential biomarkers and targets of intervention for DD. Video Abstract.
Allergic (Th2
immunophenotype) asthmatics have a heightened susceptibility to common respiratory viral infections such as human rhinovirus. Evidence suggests that the innate interferon response is ...deficient in asthmatic/atopic individuals, while other studies show no differences in antiviral response pathways. Unsensitized and OVA-sensitized/challenged Th2
(BN rats) and Th2
immunophenotype (PVG rats) animals were inoculated intranasally with attenuated mengovirus (vMC
). Sensitized animals were exposed/unexposed during the acute viral response phase. Cellular and transcriptomic profiling was performed on bronchoalveolar lavage cells. In unsensitized PVG rats, vMC
elicits a prototypical antiviral response (neutrophilic airways inflammation, upregulation of Th1/type I interferon-related pathways). In contrast, response to infection in the Th2
BN rats was associated with a radically altered intrinsic host response to respiratory viral infection, characterized by macrophage influx/Th2-associated pathways. In sensitized animals, response to virus infection alone was not altered compared to unsensitized animals. However, allergen exposure of sensitized animals during viral infection unleashes a notably exaggerated airways inflammatory response profile orders of magnitude higher in BN versus PVG rats despite similar viral loads. The co-exposure responses in the Th2
BN incorporated type I interferon/Th1, alternative macrophage activation/Th2 and Th17 signatures. Similar factors may underlie the hyper-susceptibility to infection-associated airways inflammation characteristic of the human Th2
immunophenotype.
Summary
Background
NP is a biomarker that has been used in the diagnosis, management, and prognostication of a number of cardiovascular disorders in the pediatric population. The physiological role ...of this hormone is to allow the myocardium to adapt to stress or strain imposed by a volume and/or pressure load.
Objective
The aim of this study was to determine the utility of preoperative and postoperative NP to predict outcome in pediatric patients undergoing cardiac surgery for structural congenital heart disease.
Method
We conducted a systematic review by searching three electronic databases using the search terms ‘paediatric’ or ‘pediatric’ and ‘B‐type natriuretic peptide’. Twenty peer‐reviewed papers were included in the study.
Results
Preoperative NP levels were associated with the severity of cardiac failure in several studies. Preoperative NPs also correlated with early postoperative outcome measures such as duration of cardiopulmonary bypass, duration of mechanical ventilation, presence of low cardiac output syndrome, length of stay in the intensive care unit and in one study, death. Early (within 24 h) postoperative NPs showed a stronger correlation than preoperative NPs to early postoperative adverse events.
Conclusion
NPs provide a simple, noninvasive and complementary tool to echocardiography that can be used to assist clinicians in the assessment and management of pediatric patients with congenital heart disease in the perioperative period.
The airway mucosal response to allergen in asthma involves influx of activated T helper type 2 cells and eosinophils, transient airflow obstruction, and airways hyperresponsiveness (AHR). The ...mechanism(s) underlying transient T cell activation during this inflammatory response is unclear. We present evidence that this response is regulated via bidirectional interactions between airway mucosal dendritic cells (AMDC) and T memory cells. After aerosol challenge, resident AMDC acquire antigen and rapidly mature into potent antigen-presenting cells (APCs) after cognate interactions with T memory cells. This process is restricted to dendritic cells (DCs) in the mucosae of the conducting airways, and is not seen in peripheral lung. Within 24 h, antigen-bearing mature DCs disappear from the airway wall, leaving in their wake activated interleukin 2R+ T cells and AHR. Antigen-bearing activated DCs appear in regional lymph nodes at 24 h, suggesting onward migration from the airway. Transient up-regulation of CD86 on AMDC accompanies this process, which can be reproduced by coculture of resting AMDC with T memory cells plus antigen. The APC activity of AMDC can be partially inhibited by anti-CD86, suggesting that CD86 may play an active role in this process and/or is a surrogate for other relevant costimulators. These findings provide a plausible model for local T cell activation at the lesional site in asthma, and for the transient nature of this inflammatory response.
Summary
Introduction: The primary objective of this noncomparative study was to evaluate the pharmacokinetics of ropivacaine during a 48–72‐h continuous epidural infusion of ropivacaine in children ...under 1 year. The secondary objectives were to assess efficacy and safety.
Methods: Neonates and infants (ASA I–III, gestational age ≥37 weeks, ≥2.5 kg, scheduled for major abdominal or thoracic surgery) were included and separated into age groups: 0–30 (neonate), 31–90, 91–180, and 181–365 days. Ethics committee approval and informed parental consent were obtained before inclusion. An epidural catheter was introduced under general anesthesia at the appropriate dermatomal level. An initial bolus dose (0.9–2.0 mg·kg−1 of ropivacaine 0.2%) was followed by an epidural infusion (0.2 mg·kg−1·h−1 for infants <180 days or 0.4 mg·kg−1·h−1 for infants >180 days). Plasma samples were collected every 12 h from 24 h, and on termination of the epidural infusion. Postoperative pain was evaluated using both the Objective Pain Scale and a four‐graded descriptive scale.
Results: Forty‐five infants, median age 116 (0–362) days, were included. Forty‐three and 19 patients received an infusion for at least 48 and 72 h, respectively. Satisfactory analgesia was provided in the majority, only 20 patients were given supplementary medication during the infusion. In all age groups, plasma concentrations of unbound ropivacaine leveled at 24 h, without any further increase at 48 and 72 h. Because of lower clearance of unbound ropivacaine in neonates (mean 33 ml·min−1·kg−1) than in infants above the age of 30 days (80, 124, and 163 ml·min−1·kg−1, respectively, in the age groups 31–90, 91–180, and 180–365 days), unbound ropivacaine concentrations at the end of infusion were higher in neonates median 0.10 mg·l−1 (0.04–0.21 mg·l−1) than in infants >30 days median 0.03 mg·l−1 (0.003–0.10 mg·l−1).
Conclusion: Epidural infusions (0.2–0.4 mg·kg−1·h−1 ropivacaine) provided satisfactory pain relief in neonates and infants under 1 year. As plasma concentrations of unbound ropivacaine were not influenced by the duration of the infusion, ropivacaine can be safely used for postoperative epidural infusion for 48–72 h. Levels of unbound ropivacaine were higher in the neonates than in the infants, but were below threshold concentrations for CNS toxicity in adults (≥0.35 mg·l−1). This should not preclude the use of ropivacaine infusions in neonates but suggests a need for caution during the first weeks of life.
PDF
