TPN‐associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways

Recent studies suggest a close interaction between epidermal growth factor (EGF) and TLR signaling in the modulation of intestinal epithelial cell (IEC) proliferation; however, how these signaling pathways adjust IEC proliferation is poorly understood. We utilized a model of total parenteral nutrition (TPN), or enteral nutrient deprivation, to study this interaction as TPN results in mucosal atrophy due to decreased IEC proliferation and increased apoptosis. We identified the novel finding of decreased mucosal atrophy in TLR4 knockout (TLR4KO) mice receiving TPN. We hypothesized that EGF signaling is preserved in TLR4KO‐TPN mice and prevents mucosal atrophy. C57B1/6 and strain‐matched TLR4KO mice were provided either enteral feeding or TPN. IEC proliferation and apoptosis were measured. Cytokine and growth factor abundances were detected in both groups. To examine interdependence of these pathways, ErbB1 pharmacologic blockade was used. The marked decline in IEC proliferation with TPN was nearly prevented in TLR4KO mice, and intestinal length was partially preserved. EGF was significantly increased, and TNF‐α decreased in TLR4KO‐TPN versus wild‐type (WT)‐TPN mice. Apoptotic positive crypt cells were 15‐fold higher in WT‐TPN versus TLR4KO‐TPN mice. Bcl‐2 was significantly increased in TLR4KOTPN mice, while Bax decreased 10‐fold. ErbB1 blockade prevented this otherwise protective effect in TLR4KO‐sTPN mice. TLR4 blockade significantly prevented TPN‐associated atrophy by preserving proliferation and preventing apoptosis. This is driven by a reduction in TNF‐α abundance and increased EGF. Potential manipulation of this regulatory pathway may have significant clinical potential to prevent TPN‐associated atrophy.—Freeman, J. J., Feng, Y., Demehri, F. R., Dempsey, P. J., Teitelbaum, D. H. TPN‐associated intestinal epithelial cell atrophy is modulated by TLR4/EGF signaling pathways. FASEB J. 29, 2943‐2958 (2015). www.fasebj.orgPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154328/1/fsb2fj14269480.pd

Preliminary Evaluation of MapReduce for High-Performance Climate Data Analysis

MapReduce is an approach to high-performance analytics that may be useful to data intensive problems in climate research. It offers an analysis paradigm that uses clusters of computers and combines distributed storage of large data sets with parallel computation. We are particularly interested in the potential of MapReduce to speed up basic operations common to a wide range of analyses. In order to evaluate this potential, we are prototyping a series of canonical MapReduce operations over a test suite of observational and climate simulation datasets. Our initial focus has been on averaging operations over arbitrary spatial and temporal extents within Modern Era Retrospective- Analysis for Research and Applications (MERRA) data. Preliminary results suggest this approach can improve efficiencies within data intensive analytic workflows

Stable isotope metabolomics of pulmonary artery smooth muscle and endothelial cells in pulmonary hypertension and with TGF-beta treatment.

Altered metabolism in pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs) contributes to the pathology of pulmonary hypertension (PH), but changes in substrate uptake and how substrates are utilized have not been fully characterized. We hypothesized stable isotope metabolomics would identify increased glucose, glutamine and fatty acid uptake and utilization in human PASMCs and PAECs from PH versus control specimens, and that TGF-β treatment would phenocopy these metabolic changes. We used 13C-labeled glucose, glutamine or a long-chain fatty acid mixture added to cell culture media, and mass spectrometry-based metabolomics to detect and quantify 13C-labeled metabolites. We found PH PASMCs had increased glucose uptake and utilization by glycolysis and the pentose shunt, but no changes in glutamine or fatty acid uptake or utilization. Diseased PAECs had increased proximate glycolysis pathway intermediates, less pentose shunt flux, increased anaplerosis from glutamine, and decreased fatty acid β-oxidation. TGF-β treatment increased glycolysis in PASMCs, but did not recapitulate the PAEC disease phenotype. In TGF-β-treated PASMCs, glucose, glutamine and fatty acids all contributed carbons to the TCA cycle. In conclusion, PASMCs and PAECs collected from PH subjects have significant changes in metabolite uptake and utilization, partially recapitulated by TGF-β treatment

Contemporary outcomes of vertebral artery injury

ObjectiveVertebral artery injury (VAI) associated with cervical trauma is being increasingly recognized with more aggressive screening. Disparate results from previous literature have led to uncertainty of the significance, natural history, and optimal therapy for VAI.MethodsTo understand the natural history and treatment outcomes from our experience, we performed a retrospective, single-center review from a level I trauma center for the previous 10 years of all VAI. Injuries were identified from search of an administrative trauma database, a resident-run working database, and all radiology dictations for the same period. All VAI were classified according to segmental involvement, Denver grading scale, and laterality. Analysis of associated injuries, demographics, neurologic outcome, mortality, length of stay, treatment plan, and follow-up imaging was also performed.ResultsFifty-one patients with VAI were identified from 2001 to 2011 from a total of 36,942 trauma admissions (0.13% incidence). Associated injuries were significant with an average New Injury Severity Score of 29.6. Penetrating trauma occurred in 14%. Cervical spine fracture was present in 88% with VAI. Diagnosis was obtained with computed tomographic angiography (CTA) in 95%. Screening was prompted by injury pattern or high-risk mechanism in all cases. Injuries classified according to the Denver grading scale were grade I = 24%, grade II = 35%, grade III = 4%, grade IV = 35%, and grade V = 2%. Distribution across segments included V1 = 18%, V2 = 67%, V3 = 31%, and V4 = 6%. Only one posterior circulation stroke was attributable to VAI. Overall mortality was 8%, with each mortality being associated with significant other organ injuries. Treatment rendered for VAI was antiplatelet therapy (50%), observation (31%), warfarin (17%), and stent (2%). There were no significant differences between treatment groups on any variable with the exception of body mass index (P = .047). Follow-up was obtained for 13% (n = 6) of survivors. The CTA demonstrated injury stability in four patients and resolution in two patients. Accuracy of the administrative trauma database was 53% compared with 96% for the resident-run working database.ConclusionsNeurologic sequelae attributable to VAI were rare. Grade of VAI or vertebral artery segment did not correlate with morbidity. We did not observe any differences in short-term outcomes between systemic anticoagulation and antiplatelet therapy. Of those patients seen at follow-up, injury resolution or stability was documented by CTA. A conservative approach with either observation or antithrombotic therapy is suggested. If the natural history of VAI includes a very low stroke rate, then therapies with a lower therapeutic index, such as systemic anticoagulation, in the severely injured trauma patient are not supported. Our search strategy urges awareness of the limitations of administrative databases for retrospective vascular study

Intraoperative radiation therapy for advanced cervical metastasis: a single institution experience

<p>Abstract</p> <p>Background</p> <p>The purpose of this study is to review our experience with the use of IORT for patients with advanced cervical metastasis.</p> <p>Methods</p> <p>Between August 1982 and July 2007, 231 patients underwent neck dissections as part of initial therapy or as salvage treatment for advanced cervical node metastases resulting from head and neck malignancies. IORT was administered as a single fraction to a dose of 15 Gy or 20 Gy in most pts. The majority was treated with 5 MeV electrons (112 pts, 50.5%).</p> <p>Results</p> <p>1, 3, and 5 years overall survival (OS) after surgery + IORT was 58%, 34%, and 26%, respectively. Recurrence-free survival (RFS) at 1, 3, and 5 years was 66%, 55%, and 49%, respectively. Disease recurrence was documented in 83 (42.8%) pts. The majority of recurrences were regional (38 pts), as compared to local recurrence in 20 pts and distant failures in 25 pts. There were no perioperative fatalities.</p> <p>Conclusions</p> <p>IORT results in effective local disease control at acceptable levels of toxicity. Our results support the initiation of a phase III trial comparing outcomes for patients with cervical metastasis treated with or without IORT.</p

Bostonia: The Boston University Alumni Magazine. Volume 20

Founded in 1900, Bostonia magazine is Boston University's main alumni publication, which covers alumni and student life, as well as university activities, events, and programs

Jumping to Conclusions, a Lack of Belief Flexibility and Delusional Conviction in Psychosis: A Longitudinal Investigation of the Structure, Frequency, and Relatedness of Reasoning Biases

Two reasoning biases, jumping to conclusions (JTC) and belief inflexibility, have been found to be associated with delusions. We examined these biases and their relationship with delusional conviction in a longitudinal cohort of people with schizophrenia-spectrum psychosis. We hypothesized that JTC, lack of belief flexibility, and delusional conviction would form distinct factors, and that JTC and lack of belief flexibility would predict less change in delusional conviction over time. Two hundred seventy-three patients with delusions were assessed over twelve months of a treatment trial (Garety et al., 2008). Forty-one percent of the sample had 100% conviction in their delusions, 50% showed a JTC bias, and 50%–75% showed a lack of belief flexibility. Delusional conviction, JTC, and belief flexibility formed distinct factors although conviction was negatively correlated with belief flexibility. Conviction declined slightly over the year in this established psychosis group, whereas the reasoning biases were stable. There was little evidence that reasoning predicted the slight decline in conviction. The degree to which people believe their delusions, their ability to think that they may be mistaken and to consider alternative explanations, and their hastiness in decision making are three distinct processes although belief flexibility and conviction are related. In this established psychosis sample, reasoning biases changed little in response to medication or psychological therapy. Required now is examination of these processes in psychosis groups where there is greater change in delusion conviction, as well as tests of the effects on delusions when these reasoning biases are specifically targeted

Obesity Hypertension: The Regulatory Role of Leptin

Leptin is a 16-kDa-peptide hormone that is primarily synthesized and secreted by adipose tissue. One of the major actions of this hormone is the control of energy balance by binding to receptors in the hypothalamus, leading to reduction in food intake and elevation in temperature and energy expenditure. In addition, increasing evidence suggests that leptin, through both direct and indirect mechanisms, may play an important role in cardiovascular and renal regulation. While the relevance of endogenous leptin needs further clarification, it appears to function as a pressure and volume-regulating factor under conditions of health. However, in abnormal situations characterized by chronic hyperleptinemia such as obesity, it may function pathophysiologically for the development of hypertension and possibly also for direct renal, vascular, and cardiac damage

Beyond Spheroids and Discs: Classifications of CANDELS Galaxy Structure at 1.4 < z < 2 via Principal Component Analysis

Important but rare and subtle processes driving galaxy morphology and star-formation may be missed by traditional spiral, elliptical, irregular or S\'ersic bulge/disk classifications. To overcome this limitation, we use a principal component analysis of non-parametric morphological indicators (concentration, asymmetry, Gini coefficient, $M_{20}$, multi-mode, intensity and deviation) measured at rest-frame $B$-band (corresponding to HST/WFC3 F125W at 1.4 $10^{10} M_{\odot}$) galaxy morphologies. Principal component analysis (PCA) quantifies the correlations between these morphological indicators and determines the relative importance of each. The first three principal components (PCs) capture $\sim$75 per cent of the variance inherent to our sample. We interpret the first principal component (PC) as bulge strength, the second PC as dominated by concentration and the third PC as dominated by asymmetry. Both PC1 and PC2 correlate with the visual appearance of a central bulge and predict galaxy quiescence. PC1 is a better predictor of quenching than stellar mass, as as good as other structural indicators (S\'ersic-n or compactness). We divide the PCA results into groups using an agglomerative hierarchical clustering method. Unlike S\'ersic, this classification scheme separates compact galaxies from larger, smooth proto-elliptical systems, and star-forming disk-dominated clumpy galaxies from star-forming bulge-dominated asymmetric galaxies. Distinguishing between these galaxy structural types in a quantitative manner is an important step towards understanding the connections between morphology, galaxy assembly and star-formation.Comment: 31 pages, 24 figures, accepted for publication in MNRA