Susceptibility of Pancreatic Beta Cells to Fatty Acids Is Regulated by LXR/PPARα-Dependent Stearoyl-Coenzyme A Desaturase

Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARα-agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRβ-/- and LXRαβ-/-), beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARα agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl-coA desaturase, which upon stimulation by LXR and PPARα agonists favors their desaturation and subsequent incorporation in neutral lipids

An Unusual Presentation of Congenital Esophageal Stenosis Due to Tracheobronchial Remnants in a Newborn Prenatally Diagnosed with Duodenal Atresia

Congenital esophageal stenosis due to tracheobronchial remnants is defined as an intrinsic stenosis of the esophagus caused by congenital architectural abnormalities of the esophageal wall. Although CES is present at birth, it remains asymptomatic till at the age of 4-10 months, when solid food is introduced. Here we present a case diagnosed in the neonatal period after urgent cesarean for an associated duodenal atresia complicated with perforation. There is a mutual association between duodenal atresia and congenital esophageal stenosis. When duodenal atresia is diagnosed, think of possible associated esophageal abnormalities, especially when duodenal atresia is complicated by gastric perforation prenatally.status: publishe

Thin-Section CT Features of Idiopathic Pulmonary Fibrosis Correlated with Micro-CT and Histologic Analysis

Purpose To elucidate the underlying lung changes responsible for the computed tomographic (CT) features of idiopathic pulmonary fibrosis (IPF) and to gain insight into the way IPF proceeds through the lungs and progresses over time. Materials and Methods Micro-CT studies of tissue cores obtained from explant lungs were examined and were correlated 1:1 with a CT study obtained immediately before transplantation. Samples for histologic analysis were obtained from selected cores. Results In areas with no or minimal abnormalities on CT images, small areas of increased attenuation located in or near the interlobular septa can be seen on micro-CT studies. In more involved lung areas, the number of opacities increases and opacities enlarge and approach each other along the interlobular septa, causing a fine reticular pattern on CT images. Simultaneously, air-containing structures in and around these opacities arise, corresponding with small cysts on CT images. Honeycombing is caused by a progressive increase in the number and size of these cystic structures and tissue opacities that gradually extend toward the centrilobular region and finally replace the entire lobule. At histologic analysis, the small islands of increased attenuation very likely correspond with fibroblastic foci. Near these fibroblastic foci, an abnormal adjacency of alveolar walls was seen, suggesting alveolar collapse. In later stages, normal lung tissue is replaced by a large amount of young collagen, as seen in patients with advanced fibrosis. Conclusion Fibrosis and cyst formation in patients with IPF seem to start at the periphery of the pulmonary lobule and progressively extend toward the core of this anatomic lung unit. Evidence was found that alveolar collapse might already be present in an early stage when there is only little pulmonary fibrosis. (©) RSNA, 2016.status: publishe

Morphometric Analysis of Explant Lungs in Cystic Fibrosis

RATIONALE: After repeated cycles of lung infection and inflammation, patients with cystic fibrosis (CF) evolve to respiratory insufficiency. Although histology and imaging have provided descriptive information, a thorough morphometric analysis of end-stage CF lung disease is lacking. OBJECTIVES: To quantify the involvement of small and large airways in end-stage CF. METHODS: Multidetector computed tomography (MDCT) and micro-CT were applied to 11 air-inflated CF explanted lungs and 7 control lungs to measure, count, and describe the airway and parenchymal abnormalities in end-stage CF lungs. Selected abnormalities were further investigated with thin section histology. MEASUREMENTS AND MAIN RESULTS: On MDCT, CF explanted lungs showed an increased median (interquartile range) number (631 [511-710] vs. 344 [277-349]; P = 0.003) and size of visible airways (cumulative airway diameter 217 cm [209-250] vs. 91 cm [80-105]; P < 0.001) compared with controls. Airway obstruction was seen, starting from generation 6 and increasing to 40 to 50% of airways from generation 9 onward. Micro-CT showed that the total number of terminal bronchioles was decreased (2.9/ml [2.6-4.4] vs. 5.3/ml [4.8-5.7]; P < 0.001); 49% were obstructed, and the cross-sectional area of the open terminal bronchioles was reduced (0.093 mm(2) [0.084-0.123] vs. 0.179 mm(2) [0.140-0.196]; P < 0.001). On micro-CT, 41% of the obstructed airways reopened more distally. This remodeling was confirmed on histological analysis. Parenchymal changes were also seen, mostly in a patchy and peribronchiolar distribution. CONCLUSIONS: Extensive changes of dilatation and obstruction in nearly all airway generations were observed in end-stage CF lung disease.status: publishe

Small airways pathology in idiopathic pulmonary fibrosis: a retrospective cohort study

BACKGROUND: The observation that patients with idiopathic pulmonary fibrosis (IPF) can have higher than normal expiratory flow rates at low lung volumes led to the conclusion that the airways are spared in IPF. This study aimed to re-examine the hypothesis that airways are spared in IPF using a multiresolution imaging protocol that combines multidetector CT (MDCT), with micro-CT and histology. METHODS: This was a retrospective cohort study comparing explanted lungs from patients with severe IPF treated by lung transplantation with a cohort of unused donor (control) lungs. The donor control lungs had no known lung disease, comorbidities, or structural lung injury, and were deemed appropriate for transplantation on review of the clinical files. The diagnosis of IPF in the lungs from patients was established by a multidisciplinary consensus committee according to existing guidelines, and was confirmed by video-assisted thoracic surgical biopsy or by pathological examination of the contralateral lung. The control and IPF groups were matched for age, sex, height, and bodyweight. Samples of lung tissue were compared using the multiresolution imaging approach: a cascade of clinical MDCT, micro-CT, and histological imaging. We did two experiments: in experiment 1, all the lungs were randomly sampled; in experiment 2, samples were selected from regions of minimal and established fibrosis. The patients and donors were recruited from the Katholieke Universiteit Leuven (Leuven, Belgium) and the University of Pennsylvania Hospital (Philadelphia, PA, USA). The study took place at the Katholieke Universiteit Leuven, and the University of British Columbia (Vancouver, BC, Canada). FINDINGS: Between Oct 5, 2009, and July 22, 2016, explanted lungs from patients with severe IPF (n=11), were compared with a cohort of unused donor (control) lungs (n=10), providing 240 samples of lung tissue for comparison using the multiresolution imaging approach. The MDCT specimen scans show that the number of visible airways located between the ninth generation (control 69 [SD 22] versus patients with IPF 105 [33], p=0·0023) and 14th generation (control 9 [6] versus patients with IPF 49 [28], p<0·0001) of airway branching are increased in patients with IPF, which we show by micro-CT is due to thickening of their walls and distortion of their lumens. The micro-CT analysis showed that compared with healthy (control) lung anatomy (mean 5·6 terminal bronchioles per mL [SD 1·6]), minimal fibrosis in IPF tissue was associated with a 57% loss of the terminal bronchioles (mean 2·4 terminal bronchioles per mL [SD 1·0]; p<0·0001), the appearance of fibroblastic foci, and infiltration of the tissue by inflammatory immune cells capable of forming lymphoid follicles. Established fibrosis in IPF tissue had a similar reduction (66%) in the number of terminal bronchioles (mean 1·9 terminal bronchioles per mL [SD 1·4]; p<0·0001) and was dominated by increased airspace size, Ashcroft fibrosis score, and volume fractions of tissue and collagen. INTERPRETATION: Small airways disease is a feature of IPF, with significant loss of terminal bronchioles occuring within regions of minimal fibrosis. On the basis of these findings, we postulate that the small airways could become a potential therapeutic target in IPF. FUNDING: Katholieke Universiteit Leuven, US National Institutes of Health, BC Lung Association, and Genentech.status: publishe