Delirium Prevention and Management in Frail Surgical Patients.

Delirium, an acute, fluctuating impairment in cognition and awareness, is one of the most common causes of postoperative brain dysfunction. It is associated with increased hospital length of stay, health care costs, and mortality. There is no FDA-approved treatment of delirium, and management relies on symptomatic control. Several preventative techniques have been proposed, including the choice of anesthetic agent, preoperative testing, and intraoperative monitoring. Frailty, a state of increased vulnerability to adverse events, is an independent and potentially modifiable risk factor for the development of delirium. Diligent preoperative screening techniques and implementation of prevention strategies could help improve outcomes in high-risk patients.

Is there any diagnostic value of anteroposterior chest radiography in predicting cardiac chamber enlargement?

The anteroposterior (AP) portable chest radiograph is routinely performed to evaluate cardiopulmonary status, however heart size can be misrepresented by inherent technical factors. Our aim was to determine diagnostic accuracy of cardiothoracic ratio (CTR) on AP chest radiographs relative to echocardiography, as well as relative to axial computed tomography (CT) and frontal CT scout images in predicting cardiac chamber enlargement. 200 subjects with both chest CT and AP chest radiograph within 1 month were retrospectively identified. Patients with pericardial effusion or obscured heart borders were excluded. 130 of these subjects had also undergone echocardiography. Transverse diameters of the heart and thorax were used to calculate CTRs on AP chest radiograph, scout CT, and axial CT images. A second reader was used to verify measurement accuracy and reproducibility. Statistical analysis of CTRs for AP chest radiograph, CT scout, and axial CT images were calculated using echocardiography as gold standard. AP chest radiographs had higher CTR values than axial and scout CT images (by 0.075, p < 0.001), larger measured heart diameters by approximately 3 cm (p < 0.001), and larger thoracic diameters by approximately 2 cm (p < 0.001). CTRs on AP chest radiographs calculated with a cutoff of 0.50 had sensitivity of 86% and specificity of 32%. Sensitivity and specificity were 61% and 66% respectively when using a cutoff of 0.55, and 34% and 92% respectively when using a cutoff of 0.60. A CTR of 60% is more appropriate than 50-55% when evaluating an AP chest radiograph for cardiac chamber enlargement due to its much higher specificity.

Genomic and physiological characterization and description of Marinobacter gelidimuriae sp. nov., a psychrophilic, moderate halophile from Blood Falls, an antarctic subglacial brine.

Antarctic subice environments are diverse, underexplored microbial habitats. Here, we describe the ecophysiology and annotated genome of a Marinobacter strain isolated from a cold, saline, iron-rich subglacial outflow of the Taylor Glacier, Antarctica. This strain (BF04_CF4) grows fastest at neutral pH (range 6-10), is psychrophilic (range: 0°C-20°C), moderately halophilic (range: 0.8%-15% NaCl) and hosts genes encoding potential low temperature and high salt adaptations. The predicted proteome suggests it utilizes fewer charged amino acids than a mesophilic Marinobacter strain. BF04_CF4 has increased concentrations of membrane unsaturated fatty acids including palmitoleic (33%) and oleic (27.5%) acids that may help maintain cell membrane fluidity at low temperatures. The genome encodes proteins for compatible solute biosynthesis and transport, which are known to be important for growth in saline environments. Physiological verification of predicted metabolic functions demonstrate BF04_CF4 is capable of denitrification and may facilitate iron oxidation. Our data indicate that strain BF04_CF4 represents a new Marinobacter species, Marinobacter gelidimuriae sp. nov., that appears well suited for the subglacial environment it was isolated from. Marinobacter species have been isolated from other cold, saline environments in the McMurdo Dry Valleys and permanently cold environments globally suggesting that this lineage is cosmopolitan and ecologically relevant in icy brines.

Pharmacologic inhibition of lactate production prevents myofibroblast differentiation.

Myofibroblasts are one of the primary cell types responsible for the accumulation of extracellular matrix in fibrosing diseases, and targeting myofibroblast differentiation is an important therapeutic strategy for the treatment of pulmonary fibrosis. Transforming growth factor-ß (TGF-ß) has been shown to be an important inducer of myofibroblast differentiation. We previously demonstrated that lactate dehydrogenase and its metabolic product lactic acid are important mediators of myofibroblast differentiation, via acid-induced activation of latent TGF-ß. Here we explore whether pharmacologic inhibition of LDH activity can prevent TGF-ß-induced myofibroblast differentiation. Primary human lung fibroblasts from healthy patients and those with pulmonary fibrosis were treated with TGF-ß and or gossypol, an LDH inhibitor. Protein and RNA were analyzed for markers of myofibroblast differentiation and extracellular matrix generation. Gossypol inhibited TGF-ß-induced expression of the myofibroblast marker α-smooth muscle actin (α-SMA) in a dose-dependent manner in both healthy and fibrotic human lung fibroblasts. Gossypol also inhibited expression of collagen 1, collagen 3, and fibronectin. Gossypol inhibited LDH activity, the generation of extracellular lactic acid, and the rate of extracellular acidification in a dose-dependent manner. Furthermore, gossypol inhibited TGF-ß bioactivity in a dose-dependent manner. Concurrent treatment with an LDH siRNA increased the ability of gossypol to inhibit TGF-ß-induced myofibroblast differentiation. Gossypol inhibits TGF-ß-induced myofibroblast differentiation through inhibition of LDH, inhibition of extracellular accumulation of lactic acid, and inhibition of TGF-ß bioactivity. These data support the hypothesis that pharmacologic inhibition of LDH may play an important role in the treatment of pulmonary fibrosis.

Normal Human Lung Epithelial Cells Inhibit Transforming Growth Factor-ß Induced Myofibroblast Differentiation via Prostaglandin E2.

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease with very few effective treatments. The key effector cells in fibrosis are believed to be fibroblasts, which differentiate to a contractile myofibroblast phenotype with enhanced capacity to proliferate and produce extracellular matrix. The role of the lung epithelium in fibrosis is unclear. While there is evidence that the epithelium is disrupted in IPF, it is not known whether this is a cause or a result of the fibroblast pathology. We hypothesized that healthy epithelial cells are required to maintain normal lung homeostasis and can inhibit the activation and differentiation of lung fibroblasts to the myofibroblast phenotype. To investigate this hypothesis, we employed a novel co-culture model with primary human lung epithelial cells and fibroblasts to investigate whether epithelial cells inhibit myofibroblast differentiation. MEASUREMENTS AND MAIN RESULTS: In the presence of transforming growth factor (TGF)-ß, fibroblasts co-cultured with epithelial cells expressed significantly less α-smooth muscle actin and collagen and showed marked reduction in cell migration, collagen gel contraction, and cell proliferation compared to fibroblasts grown without epithelial cells. Epithelial cells from non-matching tissue origins were capable of inhibiting TGF-ß induced myofibroblast differentiation in lung, keloid and Graves' orbital fibroblasts. TGF-ß promoted production of prostaglandin (PG) E2 in lung epithelial cells, and a PGE2 neutralizing antibody blocked the protective effect of epithelial cell co-culture. CONCLUSIONS: We provide the first direct experimental evidence that lung epithelial cells inhibit TGF-ß induced myofibroblast differentiation and pro-fibrotic phenotypes in fibroblasts. This effect is not restricted by tissue origin, and is mediated, at least in part, by PGE2. Our data support the hypothesis that the epithelium plays a crucial role in maintaining lung homeostasis, and that damaged and/ or dysfunctional epithelium contributes to the development of fibrosis.