The neglected twin: Nummular eczema is a variant of atopic dermatitis with codominant TH2/TH17 immune response.

BACKGROUND: Nummular eczema (NE) is a common chronic inflammatory skin disease characterized by multiple, pruritic, discoid-shaped lesions. Since the underlying immune mechanisms are not fully understood, it is unclear whether NE should be regarded as variant of atopic dermatitis (AD) or a distinct disease. OBJECTIVE: We compared the clinical, histopathologic, and molecular signatures of NE with that of type 2 and type 3 skin diseases. METHODS: We performed bulk RNA sequencing as well as histologic and clinical studies in lesional and nonlesional skin biopsy specimens from NE (n = 50), AD (n = 47), and psoriasis (n = 90) patients. RESULTS: NE displayed typical hallmarks of AD, such as an impaired epidermal barrier, microbial colonization, spongiosis, and eosinophil infiltration, but also aspects of psoriasis, including increased epidermal thickness, number of Ki-67+ cells, and neutrophilic infiltration. At the gene expression level, neutrophil-attracting cytokines (IL19, CXCL8, CXCL5) were upregulated, whereas TH2-related cytokines (IL13, CCL17, CCL18, CCL26, CCL27) were similarly expressed in NE compared to AD. Principal component analysis of transcriptome data from lesional skin showed that AD and NE cluster together distinct of psoriasis. In line with this, an established molecular classifier identified NE as AD rather than psoriasis. Finally, we demonstrated clinical and molecular efficacy of dupilumab treatment in NE. CONCLUSION: NE shows overlapping type 2 and type 3 immune signatures, while type 2 immunity predominates and should be the primary target of specific therapeutic interventions. This supports the view of NE as a variant of AD.

Predicting persistence of atopic dermatitis in children using clinical attributes and serum proteins.

BACKGROUND: Atopic dermatitis (AD) is the most common inflammatory skin disease in children, with 30% of all those diagnosed developing chronic or relapsing disease by adolescence. Such disease persistence cannot yet be predicted. The aim of the present study was to predict the natural course of AD using clinical parameters and serum proteins. METHODS: Sera of 144 children with AD (age 0-3 years) were analyzed for IgE and 33 cytokines, chemokines, and growth factors. Patient disease course until the age of 7 years was assessed retrospectively. Unsupervised k-means clustering was performed to define disease endotypes. Identified factors associated with AD persistence at the age of 7 years were validated in children with AD in an independent cohort (LISA Munich; n = 168). Logistic regression and XGBoosting methods followed by cross-validation were applied to predict individual disease outcomes. RESULTS: Three distinct endotypes were found in infancy, characterized by a unique inflammatory signature. Factors associated with disease persistence were disease score (SCORAD), involvement of the limbs, flexural lesion distribution at the age of 3 years, allergic comorbidities, and disease exacerbation by the trigger factors stress, pollen exposure, and change in weather. Persistence was predicted with a sensitivity of 81.8% and a specificity of 82.4%. Factors with a high impact on the prediction of persistence were SCORAD at the age of 3 years, trigger factors, and low VEGF serum levels. CONCLUSION: Atopic dermatitis in infancy comprises three immunological endotypes. Disease persistence can be predicted using serum cytokines and clinical variables.

ADAR1 Is Required for Dendritic Cell Subset Homeostasis and Alveolar Macrophage Function.

RNA editing by adenosine deaminases acting on dsRNA (ADAR) has become of increasing medical relevance, particularly because aberrant ADAR1 activity has been associated with autoimmunity and malignancies. However, the role of ADAR1 in dendritic cells (DC), representing critical professional APCs, is unknown. We have established conditional murine CD11c Cre-mediated ADAR1 gene ablation, which did not induce general apoptosis in CD11c+ cells but instead manifests in cell type-specific effects in DC subpopulations. Bone marrow-derived DC subset analysis revealed an incapacity to differentiate CD103 DC+ in both bulk bone marrow and purified pre-DC lineage progenitor assays. ADAR1 deficiency further resulted in a preferential systemic loss of CD8+/CD103+ DCs, revealing critical dependency on ADAR1, whereas other DC subpopulations were moderately affected or unaffected. Additionally, alveolar macrophages were depleted and dysfunctional, resembling pulmonary alveolar proteinosis. These results reveal an unrecognized role of ADAR1 in DC subset homeostasis and unveils the cell type-specific effects of RNA editing.

Toll-like receptor 7/8 agonists stimulate plasmacytoid dendritic cells to initiate TH17-deviated acute contact dermatitis in human subjects.

BACKGROUND: 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. OBJECTIVE: We sought to investigate the potential of a human imiquimod patch test model to resemble human psoriasis. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Anesthesia-related and perioperative mortality: An audit of 8493 cases at a tertiary pediatric teaching hospital in South Africa.

AIM: This study aimed to quantify the incidence of anesthesia-related and perioperative mortality at a large tertiary pediatric hospital in South Africa. METHODS: This study included all children aged <18 years who died prior to discharge from hospital and within 30 days of their last anesthetic at the Red Cross War Memorial Children's Hospital between January 1, 2015 to December 31, 2015. A panel of three senior anesthetists reviewed each death to reach a consensus as to whether: (i) anesthesia caused the death; (ii) anesthesia may have contributed to or influenced the timing of death; or (iii) anesthesia was entirely unrelated to the death. RESULTS: There were 47 deaths within 30 days of anesthesia prior to discharge from hospital during this 12-month period. The in-hospital mortality within 24 h of administration of anesthesia was 16.5 per 10 000 cases (95% confidence intervals [CI]=7.8-25.1) and within 30 days of administration of anesthesia was 55.3 per 10 000 cases (95% CI=39.5-71.2). Age under 1 year (OR 4.5; 95% CI=2.5-8.0, P=.012) and cardiac surgery and interventional cardiology procedures (OR 2.5; 95% CI=1.2-5.2, P<.01) were both independent predictors of increased risk of perioperative mortality. CONCLUSION: The overall 24-h and 30-day anesthesia-related and in-hospital perioperative mortality rates in our study are comparable with other similar studies from tertiary pediatric centers.

A novel molecular disease classifier for psoriasis and eczema.

Novel specific therapies for psoriasis and eczema have been developed, and they mark a new era in the treatment of these complex inflammatory skin diseases. However, within their broad clinical spectrum, psoriasis and eczema phenotypes overlap making an accurate diagnosis impossible in special cases, not to speak about predicting the clinical outcome of an individual patient. Here, we present a novel robust molecular classifier (MC) consisting of NOS2 and CCL27 gene that diagnosed psoriasis and eczema with a sensitivity and specificity of >95% in a cohort of 129 patients suffering from (i) classical forms; (ii) subtypes; and (iii) clinically and histologically indistinct variants of psoriasis and eczema. NOS2 and CCL27 correlated with clinical and histological hallmarks of psoriasis and eczema in a mutually antagonistic way, thus highlighting their biological relevance. In line with this, the MC could be transferred to the level of immunofluorescence stainings for iNOS and CCL27 protein on paraffin-embedded sections, where patients were diagnosed with sensitivity and specificity >88%. Our MC proved superiority over current gold standard methods to distinguish psoriasis and eczema and may therefore build the basis for molecular diagnosis of chronic inflammatory skin diseases required to establish personalized medicine in the field.

A novel approach to ductal spasm during percutaneous device occlusion of patent ductus arteriosus.

Ductal spasm is a rare yet important complication of device occlusions of patent ductus arteriosus. Spasm may result in failure of the procedure, under-sizing of the device, or embolisation of the implanted device as the spasm resolves after the procedure. We describe a novel protocol that rapidly and completely reversed the spasm in eight prematurely born infants who experienced ductal spasm during cardiac catheterisations for patent ductus arteriosus occlusion. In total, eight infants born between 25 and 34 weeks of gestation presented for transcatheter patent ductus arteriosus occlusion between 13 and 87 months of age. All eight patients experienced ductal spasm either immediately before, during, or soon after induction of anaesthesia or only after entering the ductus arteriosus with a catheter. After detection of the spasm, the anaesthetist, in each case, changed the mode of anaesthesia from inhaled sevoflurane to total intravenous anaesthesia with propofol, reduced the inhaled oxygen fraction to 21%, and initiated a continuous intravenous infusion of prostaglandin E1. The first two steps (total intravenous anaesthesia and FiO2 0.21) resulted in only partial relaxation of the spasm. Complete relaxation was attained after intravenous prostaglandin E1 infusions of only 10-15 minutes' duration. While maintaining this protocol, six ducti were successfully occluded and two were considered to be unsuitable for device occlusion and were referred for surgery. Ductal spasm during transcatheter occlusion may be reliably resolved and the procedure safely completed by a simple anaesthetic protocol, including the continuous infusion of intravenous prostaglandin E1.

Clinical utility of B-type natriuretic peptide (NP) in pediatric cardiac surgery--a systematic review.

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.

Reducing the risk in neonatal anesthesia.

Neonatal anesthesia is fraught with potential risk for the patient and stress for the anesthesiologist. Where possible, recognition of these risks, avoidance of, and being able to manage them appropriately, must impact positively on perioperative outcomes in this vulnerable group of patients. Good communication with the parents, as well as with other healthcare providers, is crucial to safe and successful anesthetic care.

Darier's disease exhibits a unique cutaneous microbial dysbiosis associated with inflammation and body malodour.

BACKGROUND: 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. RESULTS: 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. CONCLUSIONS: 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.

Gene Expression-Based Molecular Test as Diagnostic Aid for the Differential Diagnosis of Psoriasis and Eczema in Formalin-Fixed and Paraffin-Embedded Tissue, Microbiopsies, and Tape Strips.

Highly effective targeted therapies are available to treat noncommunicable chronic inflammatory skin diseases. In contrast, the exact diagnosis of noncommunicable chronic inflammatory skin diseases is complicated by its complex pathogenesis and clinical and histological overlap. Particularly, the differential diagnosis of psoriasis and eczema can be challenging in some cases, and molecular diagnostic tools need to be developed to support a gold standard diagnosis. The aim of this work was to develop a real-time PCR-based molecular classifier to distinguish psoriasis from eczema in formalin-fixed and paraffin-embedded-fixed skin samples and to evaluate the use of minimally invasive microbiopsies and tape strips for molecular diagnosis. In this study, we present a formalin-fixed and paraffin-embedded-based molecular classifier that determines the probability for psoriasis with a sensitivity/specificity of 92%/100%, respectively, and an area under the curve of 0.97, delivering comparable results to our previous published RNAprotect-based molecular classifier. The psoriasis probability, as well as levels of NOS2 expression, positively correlated with the disease hallmarks of psoriasis and negatively with eczema hallmarks. Furthermore, minimally invasive tape strips and microbiopsies were effectively used to differentiate psoriasis from eczema. In summary, the molecular classifier offers broad usage in pathology laboratories as well as outpatient settings and can support the differential diagnosis of noncommunicable chronic inflammatory skin diseases on a molecular level using formalin-fixed and paraffin-embedded tissue, microbiopsies, and tape strips.

Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells.

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.

Superior mesenteric artery syndrome in a patient with celiacomesenteric trunk.

Superior mesenteric artery (SMA) syndrome is an uncommon entity leading to compression of the duodenum between the aorta and the SMA. Normally the coeliac trunk and the superior mesenteric arteries have distinct origins from the abdominal aorta. The celiacomesenteric trunk (CMT) is the least frequently reported anatomic variation of all abdominal vascular anomalies. CMT denotes a common trunk of origin of the coeliac and superior mesenteric arteries. The coexistence of these anomalies has never been reported in the literature. We present a case of a 59-year-old man presenting with duodenal obstruction due to SMA syndrome with CMT. The aortomesenteric angle was 13 degrees and SMA-aorta distance was 8 mm. Patient underwent a gastrojejunostomy. After an uneventful recovery, the patient has been symptom free for 1-year follow-up.

Bidirectional interactions between antigen-bearing respiratory tract dendritic cells (DCs) and T cells precede the late phase reaction in experimental asthma: DC activation occurs in the airway mucosa but not in the lung parenchyma.

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.

Atopy-Dependent and Independent Immune Responses in the Heightened Severity of Atopics to Respiratory Viral Infections: Rat Model Studies.

Allergic (Th2high 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 Th2high (BN rats) and Th2low immunophenotype (PVG rats) animals were inoculated intranasally with attenuated mengovirus (vMC0). 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, vMC0 elicits a prototypical antiviral response (neutrophilic airways inflammation, upregulation of Th1/type I interferon-related pathways). In contrast, response to infection in the Th2high 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 Th2high 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 Th2high immunophenotype.

Altered melusin expression in the hearts of aortic stenosis patients.

BACKGROUND: The role of melusin, a necessary component in pressure-induced left-ventricular hypertrophy (LVH) in mice, has not yet been determined in human cardiac hypertrophy. We analyzed for the first time the expression and regional distribution of melusin in human LVH due to aortic stenosis (AS) and determined AKT phosphorylation as a potential downstream effector of melusin signalling. METHODS: Regional distribution of melusin was evaluated in four normal hearts. Melusin staining, gene expression and protein content were assessed in biopsies from normal and diseased hearts and melusin gene expression was correlated with LV functional changes. The pAKT/AKT ratio was determined in parallel and correlated with melusin protein content. RESULTS: In normal hearts, melusin was found in the myocytes with a uniform regional distribution. Melusin staining, mRNA and protein were significantly decreased in human AS hearts. The reduction in melusin mRNA was significantly correlated with LVEF, LVEDD and LVESD. pAKT/AKT ratio was significantly decreased in human AS and was correlated with melusin content. CONCLUSION: Reduction in melusin expression parallels the functional cardiac impairment in human AS. The simultaneous decrease of melusin and AKT phosphorylation suggests a connection between the loss of melusin and the decrease in systolic function.

QuickSmart: a basic academic skills intervention for middle school students with learning difficulties.

QuickSmart is a basic academic skills intervention designed for persistently low-achieving students in the middle years of schooling that aims to improve the automaticity of basic skills to improve higher-order processes, such as problem solving and comprehension, as measured on standardized tests. The QuickSmart instructional program consists of three structured, teacher- or teacher aide-directed, 30-minute, small-group lessons each week for approximately 26 weeks. In this study, 42 middle school students experiencing learning difficulties (LD) completed the QuickSmart reading program, and a further 42 students with LD took part in the QuickSmart mathematics program. To investigate the effects of the intervention, comparisons were made between the reading and mathematics progress of the intervention group and a group of 10 high-achieving and 10 average-achieving peers. The results indicated that although the standardized reading comprehension and mathematics scores of QuickSmart students remained below those of comparison students, they improved significantly from pretest to posttest. In contrast, the standardized scores of comparison students were not significantly different from pretest to posttest. On measures of response speed and accuracy gathered using the Cognitive Aptitude Assessment System (CAAS), QuickSmart students were able to narrow the gap between their performance and that of their high- and average-achieving peers. Implications are drawn regarding the importance of interventions that emphasize the automaticity of basic academic skills for students with learning difficulties.

Efficacy of B vitamins in lowering homocysteine in older men: maximal effects for those with B12 deficiency and hyperhomocysteinemia.

BACKGROUND AND PURPOSE: A higher plasma concentration of total homocysteine (tHcy) is associated with a greater risk of cardiovascular events. Previous studies, largely in younger individuals, have shown that B vitamins lowered tHcy by substantial amounts and that this effect is greater in people with higher tHcy and lower folate levels. METHODS: We undertook a 2-year, double-blind, placebo-controlled, randomized trial in 299 men aged > or =75 years, comparing treatment with a daily tablet containing 2 mg of folate, 25 mg of B6, and 400 microg of B12 or placebo. The study groups were balanced regarding age (mean+/-SD, 78.9+/-2.8 years), B vitamins, and tHcy at baseline. RESULTS: Among the 13% with B12 deficiency, the difference in mean changes in treatment and control groups for tHcy was 6.74 micromol/L (95% CI, 3.94 to 9.55 micromol/L) compared with 2.88 micromol/L (95% CI, 0.07 to 5.69 micromol/L) for all others. Among the 20% with hyperhomocysteinaemia, the difference between mean changes in treatment and control groups for men with high plasma tHcy compared with the rest of the group was 2.8 micromol/L (95% CI, 0.6 to 4.9 micromol/L). Baseline vitamin B12, serum folate, and tHcy were significantly associated with changes in plasma tHcy at follow-up (r=0.252, r=0.522, and r=-0.903, respectively; P=0.003, <0.001, and <0.001, respectively) in the vitamin group. CONCLUSIONS: The tHcy-lowering effect of B vitamins was maximal in those who had low B12 or high tHcy levels. Community-dwelling older men, who are likely to be deficient in B12 or have hyperhomocysteinemia, may be most likely to benefit from treatment with B vitamins.