Expression of the T Helper 17-Associated Cytokines IL-17A and IL-17F in Asthma and COPD

BACKGROUND: Asthma and COPD are characterized by airway dysfunction and inflammation. Neutrophilic airway inflammation is a common feature of COPD and is recognized in asthma, particularly in severe disease. The T helper (Th) 17 cytokines IL-17A and IL-17F have been implicated in the development of neutrophilic airway inflammation, but their expression in asthma and COPD is uncertain. METHODS: We assessed IL-17A and IL-17F expression in the bronchial submucosa from 30 subjects with asthma, 10 ex-smokers with mild to moderate COPD, and 27 nonsmoking and 14 smoking control subjects. Sputum IL-17 concentration was measured in 165 subjects with asthma and 27 with COPD. RESULTS: The median (interquartile range) IL-17A cells/mm² submucosa was increased in mild to moderate asthma (2.1 [2.4]) compared with healthy control subjects (0.4 [2.8]) but not in severe asthma (P = .04). In COPD, IL-17A(+) cells/mm² submucosa were increased (0.5 [3.7]) compared with nonsmoking control subjects (0 [0]) but not compared with smoking control subjects (P = .046). IL-17F(+) cells/mm² submucosa were increased in severe asthma (2.7 [3.6]) and mild to moderate asthma (1.6 [1.0]) compared with healthy controls subjects (0.7 [1.4]) (P = .001) but was not increased in subjects with COPD. IL-17A and IL-17F were not associated with increased neutrophilic inflammation, but IL-17F was correlated with the submucosal eosinophil count (rs = 0.5, P = .005). The sputum IL-17 concentration in COPD was increased compared with asthma (2 [0-7] pg/mL vs 0 [0-2] pg/mL, P < .0001) and was correlated with post-bronchodilator FEV₁% predicted (r = -0.5, P = .008) and FEV(1)/FVC (r = -0.4, P = .04). CONCLUSIONS: Our findings support a potential role for the Th17 cytokines IL-17A and IL-17F in asthma and COPD, but do not demonstrate a relationship with neutrophilic inflammation

Mutations in the histone methyltransferase gene KMT2B cause complex early-onset dystonia.

Histone lysine methylation, mediated by mixed-lineage leukemia (MLL) proteins, is now known to be critical in the regulation of gene expression, genomic stability, cell cycle and nuclear architecture. Despite MLL proteins being postulated as essential for normal development, little is known about the specific functions of the different MLL lysine methyltransferases. Here we report heterozygous variants in the gene KMT2B (also known as MLL4) in 27 unrelated individuals with a complex progressive childhood-onset dystonia, often associated with a typical facial appearance and characteristic brain magnetic resonance imaging findings. Over time, the majority of affected individuals developed prominent cervical, cranial and laryngeal dystonia. Marked clinical benefit, including the restoration of independent ambulation in some cases, was observed following deep brain stimulation (DBS). These findings highlight a clinically recognizable and potentially treatable form of genetic dystonia, demonstrating the crucial role of KMT2B in the physiological control of voluntary movement.Funding for the project was provided by the Wellcome Trust for UK10K (WT091310) and DDD Study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund [grant number HICF-1009-003] - see www.ddduk.org/access.html for full acknowledgement. This work was supported in part by the Intramural Research Program of the National Human Genome Research Institute and the Common Fund, NIH Office of the Director. This work was supported in part by the German Ministry of Research and Education (grant nos. 01GS08160 and 01GS08167; German Mental Retardation Network) as part of the National Genome Research Network to A.R. and D.W. and by the Deutsche Forschungsgemeinschaft (AB393/2-2) to A.R. Brain expression data was provided by the UK Human Brain Expression Consortium (UKBEC), which comprises John A. Hardy, Mina Ryten, Michael Weale, Daniah Trabzuni, Adaikalavan Ramasamy, Colin Smith and Robert Walker, affiliated with UCL Institute of Neurology (J.H., M.R., D.T.), King’s College London (M.R., M.W., A.R.) and the University of Edinburgh (C.S., R.W.)

Rechargeable Deep Brain Stimulators in the Management of Paediatric Dystonia:Well Tolerated with a Low Complication Rate

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; Deep brain stimulation (DBS) is a recognised method of treatment for primary and secondary dystonia. The size of non-rechargeable batteries has limited their use in small children. Our severe dystonia patients have required battery replacement every 20–24 months. &lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; To evaluate reliability, care burden, patients’ satisfaction and complications related to the rechargeable neurostimulator Activa® RC (launched by Medtronic in Europe in autumn 2008). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Complications were recorded prospectively, and a questionnaire on neurostimulator maintenance, care burden and parental satisfaction was applied to all patients with at least 3 months of follow-up. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; 30 Activa RCs were implanted between December 2008 and June 2010, 25 with a follow-up of 3–17 months (mean 10); the mean patient’s age at surgery was 11.1 years; 22/25 questionnaires were completed. All families achieved good standards of recharging. Caregivers were responsible for recharging in 82% of cases. With higher parameters of stimulation, recharging time was longer than initially recommended by the manufacturer. All but one family would recommend Activa RC to other patients. Transient recharging problems were the most common complication (36% of cases). Infection/skin erosion occurred in 8% of cases, self-resolving early seroma in 20%. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Activa was found to offer reliable stimulation with a low rate of significant complications and a suitable treatment option for children with dystonia.</jats:p

Bilateral subthalamic nucleus deep brain stimulation for refractory total body dystonia secondary to metabolic autopallidotomy in a 4-year-old boy with infantile methylmalonic acidemia

The methylmalonic acidemias (MMAs) are a group of inborn errors of metabolism resulting in the accumulation of methylmalonic acid in body tissues and fluids. A recognized complication of MMA is bilateral liquefaction of the globus pallidi, resulting in a fulminant total body dystonia of childhood often refractory to medical treatment. This case of total body dystonia due to MMA in a 4-year-old boy had been medically refractory for 15 months. Complete metabolic destructive liquefaction of the pallidi, that is, autopallidotomy, necessitated an alternative, bilateral subthalamic nucleus (STN) target for deep brain stimulation (DBS) with a marked improvement in dystonia and reduction in pain. The case illustrates the efficacy of STN DBS in this condition and the technical challenges in targeting the STN in a small child.</jats:p