The effects of weekly augmentation therapy in patients with PiZZ α1-antitrypsin deficiency

ST Schmid,1 J Koepke,1 M Dresel,1 A Hattesohl,1 E Frenzel,2 J Perez,3 DA Lomas,4 E Miranda,5 T Greulich,1 S Noeske,1 M Wencker,6 H Teschler,6 C Vogelmeier,1 S Janciauskiene,2,* AR Koczulla1,*1Department of Internal Medicine, Division for Pulmonary Diseases, University Hospital Marburg, Marburg, Germany; 2Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; 3Department of Cellular Biology, University of Malaga, Malaga, Spain; 4Department of Medicine, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom; 5Department of Biology and Biotechnology, Istituto Pasteur – Fondazione Cenci Bolognetti, Sapienza University of Rome, Rome, Italy; 6Department of Pneumology, West German Lung Clinic, Essen University Hospital, Essen, Germany*These authors contributed equally to this workBackground: The major concept behind augmentation therapy with human α1-antitrypsin (AAT) is to raise the levels of AAT in patients with protease inhibitor phenotype ZZ (Glu342Lys)-inherited AAT deficiency and to protect lung tissues from proteolysis and progression of emphysema.Objective: To evaluate the short-term effects of augmentation therapy (Prolastin®) on plasma levels of AAT, C-reactive protein, and chemokines/cytokines.Materials and methods: Serum and exhaled breath condensate were collected from individuals with protease inhibitor phenotype ZZ AAT deficiency-related emphysema (n = 12) on the first, third, and seventh day after the infusion of intravenous Prolastin. Concentrations of total and polymeric AAT, interleukin-8 (IL-8), monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, vascular endothelial growth factor, and C-reactive protein were determined. Blood neutrophils and primary epithelial cells were also exposed to Prolastin (1 mg/mL).Results: There were significant fluctuations in serum (but not in exhaled breath condensate) levels of AAT polymers, IL-8, monocyte chemotactic protein-1, IL-6, tumor necrosis factor- α, and vascular endothelial growth factor within a week of augmentation therapy. In general, augmented individuals had higher AAT and lower serum levels of IL-8 than nonaugmented subjects. Prolastin added for 3 hours to neutrophils from protease inhibitor phenotype ZZ individuals in vitro reduced IL-8 release but showed no effect on cytokine/chemokine release from human bronchial epithelial cells.Conclusion: Within a week, augmentation with Prolastin induced fluctuations in serum levels of AAT polymers and cytokine/chemokines but specifically lowered IL-8 levels. It remains to be determined whether these effects are related to the Prolastin preparation per se or to the therapeutic efficacy of augmentation with AAT.Keywords: Prolastin, augmentation therapy, cytokines, IL-8, exhaled breath condensate, neutrophil

Abnormal activation of the motor cortical network in idiopathic scoliosis demonstrated by functional MRI

The aetiology of idiopathic scoliosis (IS) remains unknown, but there is growing support for the possibility of an underlying neurological disorder. Functional magnetic resonance imaging (fMRI) can characterize the abnormal activation of the sensorimotor brain network in movement disorders and could provide further insights into the neuropathogenesis of IS. Twenty subjects were included in the study; 10 adolescents with IS (mean age of 15.2, 8 girls and 2 boys) and 10 age-matched healthy controls. The average Cobb angle of the primary curve in the IS patients was 35° (range 27°–55°). All participants underwent a block-design fMRI experiment in a 1.5-Tesla MRI scanner to explore cortical activation following a simple motor task. Rest periods alternated with activation periods during which participants were required to open and close their hand at an internally paced rate of approximately 1 Hz. Data were analyzed with Statistical Parametric Mapping (SPM5) including age, sex and laterality as nuisance variables to minimise the presence of bias in the results. Compared to controls, IS patients showed significant increases in blood oxygenation level dependent (BOLD) activity in contralateral supplementary motor area when performing the motor task with either hand. No significant differences were observed when testing between groups in the functional activation in the primary motor cortex, premotor cortex and somatosensory cortex. Additionally, the IS group showed a greater interhemispheric asymmetry index than the control group (0.30 vs. 0.13, p < 0.001). This study demonstrates an abnormal pattern of brain activation in secondary motor areas during movement execution in patients with IS. These findings support the hypothesis that a sensorimotor integration disorder underlies the pathogenesis of IS