PurposeAlthough the role of the angiotensin II type 2 (AT2) receptor in acute lung injury is not yet completely understood, a protective role of this receptor subtype has been suggested. We hypothesized that, in a rodent model of acute lung injury, stimulation of the AT2 receptor with the direct agonist Compound 21 (C21) might have a beneficial effect on pulmonary inflammation and might improve pulmonary gas exchange.Materials and methodsMale adult rats were divided into a treatment group that received pulmonary lavage followed by mechanical ventilation (LAV, n=9), a group receiving pulmonary lavage, mechanical ventilation, and direct stimulation of the AT2 receptor with C21 (LAV+C21, n=9), and a control group that received mechanical ventilation only (control, n=9). Arterial blood gas analysis was performed every 30 min throughout the 240-min observation period. Lung tissue and plasma samples were obtained at 240 min after the start of mechanical ventilation. Protein content and surface activity of bronchoalveolar lavage fluid were assessed and the wet/dry-weight ratio of lungs was determined. Transcriptional and translational regulation of pro- and antiinflammatory cytokines IL-1β, tumor necrosis factor-alpha, IL-6, IL-10, and IL-4 was determined in lungs and in plasma.ResultsPulmonary lavage led to a significant impairment of gas exchange, the formation of lung edema, and the induction of pulmonary inflammation. Protein content of lavage fluid was increased and contained washed-out surfactant. Direct AT2 receptor stimulation with C21 led to a significant inhibition of tumor necrosis factor-alpha and IL-6 expressions in the lungs, whereas the expressions of IL-1, IL-10, and IL-4 remained unchanged. During the 240-min observation period, AT2 receptor stimulation did not improve pulmonary gas exchange or lung edema.ConclusionIn this rodent model of acute lung injury after repeated pulmonary lavage, AT2 receptor stimulation attenuates pulmonary inflammation but does not improve gas exchange.

This model of ALI applied in rats can induce pulmonary inflammation. The model might be used to develop therapeutic strategies that target pulmonary inflammation in ALI.

/Herdecke University Hospital. Contrary to his brother the boy presented dystrophic at birth (1.715 g birth weight; 150 g below 3rd percentile) and developed adverse gastrointestinal conditions within the first 2 months of life. These included chronic mucosal inflammation and oedematous lamina propria in the intestine, which contributed to intractable diarrhoea. At an age of 7 months the infant eventually died of enteral haemorrhages and liver failure. Further anamnesis revealed several similar fatalities in the familial clan with reportedly frequent parental consanguinity. Intractable chronic diarrhoea in infancy are heterogeneous disorders challenging for diagnostics and therapy. Despite extensive diagnostic approaches the etiology of many cases remains elusive. Investigating putatively underlying genetic disorders might clarify many cases. ResultsTo contribute to the diagnosis we performed whole exome sequencing of the affected infant as well as his twin brother and parents. We identified a suspicious nonsynonymous single nucleotide polymorphism (SNP) in the integrin beta-6 gene (ITGB6G1312A) entailing a V438M substitution. This SNP is very rare in the G1000 cohort and predicted being potentially harmful. The allelic distribution in the genotyped family members fit well with an autosomal recessive inheritance scheme. We performed computational biological and molecular biological analyses on the α V β6 integrin receptor function suggesting that the integrin α V β6 dimerization could be impaired, potentially causing a loss of α V β6 function in wound healing and epithelial tissue integrity. Conclusions Our study provides a starting point for elucidating integrin α V β6 function and for understanding a pathomechanistical relevance of ITGB6V438M. Consent for publicationThe authors have written informed consent from the patients' guardian/parent. Metabolic treatment according to current guideline recommendations has significantly improved neurological outcome. However, cognitive functions have not yet been studied in detail. Methods In a cross-sectional design, 30 patients detected by newborn screening (n = 13), high-risk screening (n = 3) or targeted metabolic testing (n = 14) were studied for simple reaction time (SRT), continuous performance (CP), visual working memory (VWM), visual-motor coordination (Tracking) and visual search (VS). Dystonia (n = 13 patients) was categorized using the Barry-Albright-Dystonia Scale (BADS). Patients were compared with 196 healthy controls. Developmental functions of cognitive performances were analysed using a negative exponential function model. Results BADS scores correlated with speed tests but not with tests measuring stability or higher cognitive functions without time constraints. Developmental functions of GA-I patients significantly differed from controls for SRT and VS but not for VWM and showed obvious trends for CP and Tracking. Dystonic patients were slower in SRT and CP but reached their asymptote of performance similar to asymptomatic patients and controls in all...