tbuckley/cabot-search huggingface dataset:
Glucocorticoid Treatment Prevents Progressive Myocardial Dysfunction Resulting From Experimental Coronary Microembolization
Authors: Andreas Skyschally, Michael Haude, Hilmar Dörge, Matthias Thielmann, Alexej Duschin, Anita van de Sand, Ina Konietzka, Astrid Büchert, Stephanie Aker, Parwis Massoudy, Rainer Schulz, Raimund Erbel, Gerd Heusch
Journal: Circulation (2004)

The frequency and importance of microembolization in patients with acute coronary syndromes and during coronary interventions have recently been appreciated. Experimental microembolization induces immediate ischemic dysfunction, which recovers within minutes. Subsequently, progressive contractile dysfunction develops over several hours and is not associated with reduced regional myocardial blood flow (perfusion-contraction mismatch) but rather with a local inflammatory reaction. We have now studied the effect of antiinflammatory glucocorticoid treatment on this progressive contractile dysfunction.Microembolization was induced by injecting microspheres (42-microm diameter) into the left circumflex coronary artery. Anesthetized dogs were followed up for 8 hours and received placebo (n=7) or methylprednisolone 30 mg/kg IV either 30 minutes before (n=7) or 30 minutes after (n=5) microembolization. In addition, chronically instrumented dogs received either placebo (n=4) or methylprednisolone (n=4) 30 minutes after microembolization and were followed up for 1 week. In acute placebo dogs, posterior systolic wall thickening was decreased from 20.0+/-2.1% (mean+/-SEM) at baseline to 5.8+/-0.6% at 8 hours after microembolization. Methylprednisolone prevented the progressive myocardial dysfunction. Increased leukocyte infiltration in the embolized myocardium was prevented only when methylprednisolone was given before microembolization. In chronic placebo dogs, progressive dysfunction recovered from 5.0+/-0.7% at 4 to 6 hours after microembolization back to baseline (19.1+/-1.6%) within 5 days. Again, methylprednisolone prevented the progressive myocardial dysfunction.Methylprednisolone, even when given after microembolization, prevents progressive contractile dysfunction.
Hedgehog Acyltransferase as a target in estrogen receptor positive, HER2 amplified, and tamoxifen resistant breast cancer cells
Authors: Armine Matevossian, Marilyn D Resh
Journal: Molecular Cancer (2015)

Hedgehog acyltransferase (Hhat) catalyzes the transfer of the fatty acid palmitate onto Sonic Hedgehog (Shh), a modification that is essential for Shh signaling activity. The Shh signaling pathway has been implicated in the progression of breast cancer. To determine the functional significance of Hhat expression in breast cancer, we used a panel of breast cancer cell lines that included estrogen receptor (ER) positive, HER2 amplified, triple negative, and tamoxifen resistant cells. We monitored both anchorage dependent and independent proliferation of these cells following depletion of Hhat with lentiviral shRNA and inhibition of Hhat activity with RU-SKI 43, a small molecule inhibitor of Hhat. Depletion of Hhat decreased anchorage-dependent and anchorage-independent proliferation of ER positive, but not triple negative, breast cancer cells. Treatment with RU-SKI 43 also reduced ER positive cell proliferation, whereas a structurally related, inactive compound had no effect. Overexpression of Hhat in ER positive cells not only rescued the growth defect in the presence of RU-SKI 43 but also resulted in increased cell proliferation in the absence of drug. Furthermore, depletion or inhibition of Hhat reduced proliferation of HER2 amplified as well as tamoxifen resistant cells. Inhibition of Smoothened had no effect on proliferation, indicating that canonical Shh signaling was not operative. Moreover, Hhat regulated the proliferation of both Shh responsive and non-responsive ER positive cells, suggesting a Shh independent function for Hhat. These data suggest that Hhat plays a critical role in ER positive, HER2 amplified, and hormone resistant breast cancer proliferation and highlights the potential promise of Hhat inhibitors for therapeutic benefit in breast cancer.
Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison
Authors: B Combe
Journal: Annals of the Rheumatic Diseases (2006)

To compare the efficacy and safety of etanercept and sulfasalazine, alone and in combination, in patients with active rheumatoid arthritis despite sulfasalazine treatment.A double-blind, randomised study in adult patients with active rheumatoid arthritis despite stable sulfasalazine (2-3 g/day) treatment. The primary end point was a 20% response by the American College of Rheumatology (ACR) criteria at 24 weeks.At baseline, the three treatment groups (sulfasalazine, n = 50; etanercept, n = 103; etanercept and sulfasalazine, n = 101) were comparable for demographic variables and disease activity. Lack of efficacy was the primary reason for discontinuation (sulfasalazine, n = 12; etanercept, n = 1; etanercept and sulfasalazine, n = 4; p<0.001). Significantly more patients receiving etanercept, alone or in combination (74% for each), achieved ACR 20 responses at 24 weeks than those receiving sulfasalazine (28%; p<0.01). Similarly, more patients in the etanercept groups achieved ACR 50 and ACR 70 responses than those in the sulfasalazine group (p<0.01). In the groups receiving etanercept, significant differences in the ACR core components were observed by week 2 compared with those receiving sulfasalazine alone (p<0.01). The incidences of several common adverse events (headache, nausea, asthenia) were lower with etanercept alone than with the combination (p<0.05), but infections and injection site reactions were higher with etanercept alone (p<0.05). The safety profiles of both etanercept treatment groups were comparable with previous experience of etanercept.For all efficacy variables assessed, etanercept alone or in combination with sulfasalazine resulted in substantial and similar improvement in disease activity from baseline to week 24 compared with sulfasalazine alone in patients with active rheumatoid arthritis despite their sulfasalazine treatment. All three treatments were generally well tolerated.
PWE-197 Is MRCP a useful Investigation where the Biliary Tree is normal on Previous Imaging?: Abstract PWE-197 Table 1
Authors: B Vadhwana, J Graby, A Yusuf, A Sergot, C Ramsey, K Monahan
Journal: Gut (2013)

<h3>Introduction</h3> Magnetic Resonance Cholangiopancreatography (MRCP) is increasingly used in the diagnosis of biliary disease, especially in stone disease. It has a high sensitivity and specificity[1] [2]; however its role in the absence of dilated biliary tree on previous imaging is not clear. The aim of this study was to determine the diagnostic yield of MRCP in patients with an undilated biliary tree. <h3>Methods</h3> We performed a retrospective observational study of MRCP studies (n = 119) performed between October 2011 and September 2012 at West Middlesex University Hospital using electronic medical records. All MRCPs were reported by a consultant radiologist. MRCP findings were correlated with the presence of dilated (but otherwise normal) or undilated biliary tree on initial imaging (USS/CT), jaundice (bilirubin &gt; 21 μmol/L) and abdominal pain. Demographics including age and gender were noted. Fisher’s exact test was used to analyse binary variables and student’s T test for continuous variables using the STATA12 statistical software <h3>Results</h3> In patients with a normal biliary tree on previous imaging the yield of MRCP was low with only 2/44 demonstrating stone or other pathology (p = 0.0002). Patient referred for MRCP without biliary tree dilatation had a median age 12 years younger (p = 0.033) and the indication was more likely to be pain (p = 0.017) but not jaundice (p = 1) and referrals were not gender related (p = 0.23). <h3>Conclusion</h3> Our study demonstrates a low diagnostic yield of MRCP in the absence of dilated biliary system on previous USS/CT. Furthermore, the presence of jaundice or abdominal pain does not help to select patients who may benefit from further biliary imaging with MRCP. Routine MRCP in patients with an undilated biliary tree on USS/CT does not appear to be indicated. <h3>Disclosure of Interest</h3> None Declared. <h3>Reference</h3> ShanmugamV, Beattie GC, Yule SR,<i> et al.</i> Is magnetic resonance cholangiopancreatography the new gold standard in biliary imaging?<i> British Journal of Radiolog</i>y (2005) 78, 888–893. Williams EJ, Green J, Bechingham I, <i>et al.</i>Guidelines on the management of common bile ductstones (CBDS). Gut 2008; 57:1004–1021.
Consumption of Hydrogenated Versus Nonhydrogenated Vegetable Oils and Risk of Insulin Resistance and the Metabolic Syndrome Among Iranian Adult Women
Authors: Ahmad Esmaillzadeh, Leila Azadbakht
Journal: Diabetes Care (2008)

Remarkably rapid increase in the prevalence of the metabolic syndrome reflects the strong impact of lifestyle factors, including diet, on its etiology. In particular, dietary intake of fat may play a role in this regard. Different types of fat have been related to insulin resistance and the metabolic syndrome, but findings are inconsistent. One specific type of dietary fatty acid that has received increased attention is trans fatty acid (TFA); higher consumption was associated with increased risk of cardiovascular disease (1) and type 2 diabetes (2). Although some studies have reported a significant association between dietary fat intake and the metabolic syndrome (3,4), to our knowledge, such analyses have not been done separately for hydrogenated and nonhydrogenated vegetable oils. Hydrogenated vegetable oils (HVOs)—rich sources of both saturated fatty acids (SFAs) and TFAs—are extensively used for cooking in Iranian homes with average per-person intake of 14g per 1,000 kcal (5). In addition to large amounts of SFAs, these products have almost 33% of total fatty acids as TFAs. In other words, 4.2% of all calories consumed by Iranians are derived from TFAs, which is about twice the amount consumed in many developed countries (5). In the current study, we investigated whether high consumption of HVOs is contributing to a high prevalence of the metabolic syndrome among Iranian women.

This cross-sectional study was conducted among Tehrani female teachers aged 40–60 years selected by a multistage cluster random sampling …
Drug metabolism in hepatosplenic schistosomiasis in the Sudan: a study with antipyrine.
Authors: M Homeida, S Y Salih, R A Branch
Journal: Gut (1978)

The disposition of antipyrine following oral administration of 1200 mg has been investigated in 10 patients with histologically confirmed hepatosplenic schistosomiasis and 11 normal subjects living in Sudan. Drug metabolising activity as assessed by antipyrine clearance was similar in patients when compared with normal controls. We conclude that antipyrine disposition is normal in patients with clinically compensated hepatosplenic schistosomiasis.
Computerised cognitive assessment of concussed Australian Rules footballers
Authors: M Makdissi, A Collie, P Maruff, D G Darby, A Bush, P McCrory, K Bennell
Journal: British Journal of Sports Medicine (2001)

"Paper and pencil" neuropsychological tests play an important role in the management of sports related concussions. They provide objective information on the athlete's cognitive function and thus facilitate decisions on safe return to sport. It has been proposed that computerised cognitive tests have many advantages over such conventional tests, but their role in this domain is yet to be established.To measure cognitive impairment after concussion in a case series of concussed Australian Rules footballers, using both computerised and paper and pencil neuropsychological tests. To investigate the role of computerised cognitive tests in the assessment and follow up of sports related concussions.Baseline measures on the Digit Symbol Substitution Test (DSST), Trail Making Test-Part B (TMT), and a simple reaction time (SRT) test from a computerised cognitive test battery (CogState) were obtained in 240 players. Tests were repeated in players who had sustained a concussive injury. A group of non-injured players were used as matched controls.Six concussions were observed over a period of nine weeks. At the follow up, DSST and TMT scores did not significantly differ from baseline scores in both control and concussed groups. However, analysis of the SRT data showed an increase in response variability and latency after concussion in the injured athletes. This was in contrast with a decrease in response variability and no change in latency on follow up of the control players (p<0.02).Increased variability in response time may be an important cognitive deficit after concussion. This has implications for consistency of an athlete's performance after injury, as well as for tests used in clinical assessment and follow up of head injuries.
A Role for Endogenous Transforming Growth Factor β1 in Langerhans Cell Biology: The Skin of Transforming Growth Factor β1 Null Mice Is Devoid of Epidermal Langerhans Cells
Authors: Teresa A. Borkowski, John J. Letterio, Andrew G. Farr, Mark C. Udey
Journal: The Journal of Experimental Medicine (1996)

Transforming growth factor β1 (TGF-β1) regulates leukocytes and epithelial cells. To determine whether the pleiotropic effects of TGF-β1, a cytokine that is produced by both keratinocytes and Langerhans cells (LC), extend to epidermal leukocytes, we characterized LC (the epidermal contingent of the dendritic cell [DC] lineage) and dendritic epidermal T cells (DETC) in TGF-β1 null (TGF-β1 −/−) mice. I-A+ LC were not detected in epidermal cell suspensions or epidermal sheets prepared from TGF-β1 −/− mice, and epidermal cell suspensions were devoid of allostimulatory activity. In contrast, TCR-γδ+ DETC were normal in number and appearance in TGF-β1 −/− mice and, importantly, DETC represented the only leukocytes in the epidermis. Immunolocalization studies revealed CD11c+ DC in lymph nodes from TGF-β1 −/− mice, although gp40+ DC were absent. Treatment of TGF-β1 −/− mice with rapamycin abrogated the characteristic inflammatory wasting syndrome and prolonged survival indefinitely, but did not result in population of the epidermis with LC. Thus, the LC abnormality in TGF-β1 −/− mice is not a consequence of inflammation in skin or other organs, and LC development is not simply delayed in these animals. We conclude that endogenous TGF-β1 is essential for normal murine LC development or epidermal localization.
Primary Melanoma of the CNS in Children Is Driven by Congenital Expression of Oncogenic <i>NRAS</i> in Melanocytes
Authors: Malin Pedersen, Heidi V.N. Küsters-Vandevelde, Amaya Viros, Patricia J.T.A. Groenen, Berta Sanchez-Laorden, Jacobus H. Gilhuis, Ilse A. van Engen-van Grunsven, Willy Renier, Jolanda Schieving, Ion Niculescu-Duvaz, Caroline J. Springer, Benno Küsters, Pieter Wesseling, Willeke A.M. Blokx, Richard Marais
Journal: Cancer Discovery (2013)

NRAS mutations are common in human melanoma. To produce a mouse model of NRAS-driven melanoma, we expressed oncogenic NRAS (NRAS(G12D)) in mouse melanocytes. When NRAS(G12D) was expressed in the melanocytes of developing embryos, it induced melanocyte proliferation and congenital melanocytic lesions reminiscent of human blue nevi but did not induce cutaneous melanoma. Unexpectedly, however, it did induce early-onset primary melanoma of the central nervous system (CNS). The tumors were rapidly proliferating and caused neurologic symptoms, rapid health deterioration, and death. NRAS is not a common driver oncogene of primary melanoma of the CNS in adults, but we report two cases of primary melanoma of the CNS in children, both of which carried oncogenic mutations in NRAS. We conclude that acquisition of somatic mutations in NRAS in CNS melanocytes is a predisposing risk factor for primary melanoma of the CNS in children, and we present a mouse model of this disease.
Hemodynamic Effects of Hypervolemia with and without Anemia
Authors: NOBLE O. FOWLER, WALTER L. BLOOM, JOHN A. WARD
Journal: Circulation Research (1958)

Hypervolemia was produced in dogs by infusion of matched whole blood or of red cells suspended in dextran. In the dogs which had received matched whole blood, bleeding with simultaneous volume replacement with dextran produced acute hypervolemic anemia. This was associated with increased cardiac output, whereas no increase of cardiac output was seen in the same animals with a comparable amount of hypervolemia without anemia. The results suggest that anemia rather than hypervolemia was the important factor in causing an increase of cardiac output in these experiments.
Heart Regeneration with Engineered Myocardial Tissue
Authors: Kareen L.K. Coulombe, Vivek K. Bajpai, Stelios T. Andreadis, Charles E. Murry
Journal: Annual Review of Biomedical Engineering (2014)

Heart disease is the leading cause of morbidity and mortality worldwide, and regenerative therapies that replace damaged myocardium could benefit millions of patients annually. The many cell types in the heart, including cardiomyocytes, endothelial cells, vascular smooth muscle cells, pericytes, and cardiac fibroblasts, communicate via intercellular signaling and modulate each other's function. Although much progress has been made in generating cells of the cardiovascular lineage from human pluripotent stem cells, a major challenge now is creating the tissue architecture to integrate a microvascular circulation and afferent arterioles into such an engineered tissue. Recent advances in cardiac and vascular tissue engineering will move us closer to the goal of generating functionally mature tissue. Using the biology of the myocardium as the foundation for designing engineered tissue and addressing the challenges to implantation and integration, we can bridge the gap from bench to bedside for a clinically tractable engineered cardiac tissue.
Abstract 148: Parkin Mediates Clearance of Dysfunctional Mitochondria via Multiple Pathways
Authors: Babette C Hammerling, Melissa Q Cortez, Rita A Hanna, Rebecca E Jimenez, Åsa B Gustafsson
Journal: Circulation Research (2014)

The ability to clear damaged mitochondria is critical to prevent unnecessary death. Studies have found that dysfunctional mitochondria are rapidly sequestered by autophagosomes and subsequently delivered to lysosomes for degradation. The E3 ubiquitin ligase Parkin has been identified as an important regulator of mitochondrial autophagy. We have previously shown that Parkin plays an important role in clearing dysfunctional mitochondria via autophagy in the heart after myocardial infarction. In this study, we have discovered that Parkin also induces clearance of mitochondria via an autophagy-independent pathway. We found that Parkin mediated clearance of damaged mitochondria in both wild type (WT) and autophagy-deficient Atg5 knockout mouse embryonic fibroblasts (MEFs) treated with the mitochondria uncoupler FCCP. Interestingly, mitochondrial clearance in both cell types was dependent on the presence of Parkin, suggesting that Parkin represents a rate-limiting step. Immunofluorescence analysis revealed that FCCP-treatment resulted in activation of the Vps34-Rab5 complex with subsequent sequestration of mitochondria inside Rab5-positive endosomes and LAMP2-positive lysosomes in Atg5-/- MEFs. The presence of mitochondria inside endosomes in Atg5-/- MEFs was confirmed by transmission electron microscopy (TEM). Pharmacological inhibition of the endosomal-lysosomal pathway with 3-methyladenine or Bafilomycin A1 caused a significant increase in FCCP-mediated cell death in Atg5-/- MEFs. Also, although BNIP3 functions as an autophagy receptor on mitochondria by interacting with LC3II on the autophagosome, it induced mitochondrial clearance in Atg5-/- MEFs via activation of the endosomal pathway. Finally, we confirmed that mitochondrial clearance occurs via both the autophagy and endosomal pathways in neonatal cardiomyocytes subjected to simulated ischemia/reperfusion (I/R). TEM analysis revealed the presence of mitochondria inside endosomes rat hearts subjected to ex vivo I/R. These data demonstrate that both autophagy and endosomal pathways contribute to clearance of damaged mitochondria in cells, and represent potential future therapeutic targets to enhance or preserve mitochondrial clearance in patients after MI.
ANTITUBERCULOUS IMMUNITY INDUCED IN MICE BY VACCINATION WITH LIVING CULTURES OF ATTENUATED TUBERCLE BACILLI
Authors: René J. Dubos, Cynthia H. Pierce, Werner B. Schaefer
Journal: The Journal of Experimental Medicine (1953)

The immunity induced in mice by vaccination with living attenuated cultures of tubercle bacilli was measured by two criteria. (a) Increase in survival time of the vaccinated animals after infection with a dose of virulent bacilli sufficient to kill all the unvaccinated controls within 10 to 20 days. (b) Difference in the number of living bacilli recovered from the spleen and lungs of vaccinated and normal animals infected with a small dose of virulent bacilli. The level of immunity induced was found to depend upon the extent of multiplication in vivo of the bacilli used for vaccination. This in turn was conditioned by the degree of attenuation characteristic of the bacterial strain used in the preparation of the vaccine, the amount of vaccine injected, the route of vaccination, and the time interval between vaccination and challenge infection. It was possible to prevent or retard the development of immunity by treating the mice in course of immunization with a drug, isoniazid, capable of interrupting the multiplication in vivo of the bacilli used as vaccine. Although immunity regularly developed and lasted for many weeks when the proper conditions of vaccination were used, the immune response was never sufficient to protect the animals against ultimate death from infection with virulent tubercle bacilli. The prolongation of life in the vaccinated mice was not consequent on a direct bactericidal effect but rather on a retarded or interrupted multiplication of the virulent bacilli in vivo. The quantitative bacteriological techniques used in the present study would appear to be of value for the analysis of certain problems of immunity, and for the appraisal of vaccines and techniques of vaccination.
Serum 25-Hydroxy Vitamin D and Insulin Resistance, Metabolic Syndrome, and Glucose Intolerance Among Arab Americans
Authors: Nicole R. Pinelli, Linda A. Jaber, Morton B. Brown, William H. Herman
Journal: Diabetes Care (2010)

To describe 25-hydroxy vitamin D (25-OH-D) levels and examine associations between 25-OH-D levels and insulin resistance (IR), metabolic syndrome (MS), and glucose intolerance in Arab Americans.