The management of airway, breathing, and circulation, and oxygen therapy and monitoring in severely ill patients before admission to intensive care units may frequently be suboptimal. Major consequences may include increased morbidity and mortality and requirement for intensive care. Possible solutions include improved teaching, establishment of medical emergency teams, and widespread debate on the structure and process of acute care.

Netherton's syndrome is a rare genodermatosis of unknown cause, which is classified as an ichthyosiform syndrome. A clinical and immunological study of seven patients with Netherton's syndrome illustrates the clinical spectrum of this disorder, the frequent association with atopy, and the absence of consistent immunological abnormalities. Failure to thrive in infancy was a feature in six of the seven patients, and was considered to be life-threatening in three. The skin disease evolved into ichthyosis linearis circumflexa in four of the seven, and the remaining three patients suffered from persistent or recurrent ichthyosiform erythroderma.

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Reactive oxygen metabolites are potent inflammatory mediators that may be involved in tissue injury in inflammatory bowel disease. To evaluate their role in inflammatory bowel disease, we investigated the effects oflowering the activities of reactive oxygen metabolites in experimental colitis induced by intracolonic administration of acetic acid in rats. Intracolonic administration of5% acetic acid caused severe inflammation (mean (SEM) inflammatory score was 24*3 (0.7) of a maximum score of 32). Acetic acid at 2-5% produced moderate inflammation (score= 17 (1.4) v 4-0 (0.5) in control rats). This lower dose was used for subsequent experiments. Specific superoxide anion scavenger methoxypolyethylene glycol:superoxide dismutase, and reactive oxygen metabolites scavenger, sulfasalazine, significantly decreased the severity of inflammation (s'cores: 8 (4.4) and 9-8 (2.2) respectively). The xanthine oxidase inhibitors, tungsten and pterin aldehyde, failed to improve inflammation but another xanthine oxidase inhibitor, aliopurinol, a compound with known superoxide anion scavenging effect, did limit the inflammation (10(2)). Inhibition ofhydroxyl radicalproduction by deferoxamine orlowering hydroxyl radical values by a scavenger, dimethyl sulfoxide, did not affect the severity of inflammation. These data suggest: (1) that reactive oxygen metabolites play an important role in experimental colitis, (2) that the xanthine oxidase pathway is not a major source of reactive oxygen metabolites in colitis, and (3) that tissue injury in experimental colitis is not caused by generation of hydroxyl radicals.

Objective. Interferon-␣ (IFN␣) has been implicated in the pathogenesis of juvenile dermatomyositis (DM). The aim of this study was to examine serum IFN␣ activity in a cohort of children with juvenile DM to determine relationships between IFN␣ and indicators of disease activity and severity.Methods. Thirty-nine children with definite/ probable juvenile DM were included in the study. Serum samples were obtained at the time of diagnosis from 18 untreated patients with juvenile DM. Second samples from 11 of these patients were obtained at 24 months, while they were receiving treatment, and third samples were obtained from 7 of these patients at 36 months. The remaining 21 children were studied 36 months after their initial diagnosis. Serum IFN␣ activity was measured using a functional reporter cell assay.Results. Patients with juvenile DM had higher serum IFN␣ activity than both pediatric and adult healthy control subjects. In untreated patients, serum IFN␣ activity was positively correlated with serum muscle enzyme levels (P < 0.05 for creatine kinase, aspartate aminotransferase, and aldolase) and inversely correlated with the duration of untreated disease (P ‫؍‬ 0.017). The tumor necrosis factor ␣ ؊308A allele was associated with higher serum IFN␣ levels only in untreated patients (P ‫؍‬ 0.030). At 36 months, serum IFN␣ levels were inversely correlated with muscle enzyme levels in those patients still requiring therapy and with the skin Disease Activity Score in those patients who had completed therapy (P ‫؍‬ 0.002).Conclusion. Serum IFN␣ activity was associated with higher serum levels of muscle-derived enzymes and a shorter duration of untreated disease in patients with newly diagnosed juvenile DM and was inversely correlated with measures of chronic disease activity at 36 months postdiagnosis. These data suggest that IFN␣ could play a role in disease initiation in juvenile DM.

Objective. Neutrophils are key immune cells participating in host defense through several mechanisms, including the formation of neutrophil extracellular traps (NETs). This study was undertaken to investigate the role of neutrophils in juvenile dermatomyositis (JDM).Methods. Electron microscopy was used to identify neutrophils in tissue. NETs were also imaged using fluorescence microscopy and quantified using a myeloperoxidase-DNA enzyme-linked immunosorbent assay (ELISA) in plasma obtained from healthy children (n = 20), disease controls (n = 29), JDM patients (n = 66), and JDM patients with history of calcifications (n = 20). Clinical data included disease activity scores and complement C4 levels. Levels of immune complexes (ICs) and calprotectin were analyzed using ELISA.Results. Using electron microscopy, neutrophils were found to infiltrate affected muscle tissue, engulfing deposited calcium crystals. Uptake of the crystals led to neutrophil activation (P < 0.01) and subsequent phosphatidylinositol 3-kinase-and NADPH oxidase-dependent but peptidylarginine deiminase 4-independent formation of NETs, which contained mitochondrial DNA (P < 0.05), as confirmed in vivo (P < 0.001) and in vitro (P < 0.01). Peripheral NET levels were associated with calcinosis (P = 0.01), ICs (P = 0.008), and interleukin-8 levels (P = 0.004). Children with JDM had impaired NET clearance (P = 0.01), associated with autoantibody profiles including melanoma differentiationassociated protein 5 (P = 0.005), and depressed complement C4 levels (r = −0.72, P = 0.002). Furthermore, children with JDM showed evidence of neutrophil activation, with elevated levels of peroxidase activity (P = 0.02) and calprotectin (P < 0.01), which were associated with disease activity (P = 0.007), and dyslipidemia (odds ratio 4.7, P < 0.05).Conclusion. We found novel mechanisms of both calcium crystal-mediated neutrophil activation and cell death in JDM pathophysiology. Targeting this pathway may reduce the frequency and extent of calcinosis, as well as prevent long-term development of comorbidities, including atherosclerosis.

We find strong familial aggregation of specific autoimmune diseases in families of children with juvenile dermatomyositis, suggesting that these conditions share pathogenic factors. Higher serum interferon-α in juvenile dermatomyositis patients with a family history of systemic lupus erythematosus suggesting that interferon-α is one such shared factor.

ResultsThe median age at diagnosis and the end of the study was 13 (range 1-84) and 82 (range 16-248) months, respectively. Three splenectomised and one non-splenectomised patients died during the total observation period of 436 on 12 May 2018 by guest. Protected by copyright.