tbuckley/cabot-search huggingface dataset:
NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB
Authors: Hengwei Zhang, Matthew J. Hilton, Jennifer H. Anolik, Stephen L. Welle, Chen Zhao, Zhenqiang Yao, Xing Li, Zhiyu Wang, Brendan F. Boyce, Lianping Xing
Journal: Journal of Clinical Investigation (2014)

NOTCH-dependent signaling pathways are critical for normal bone remodeling; however, it is unclear if dysfunctional NOTCH activation contributes to inflammation-mediated bone loss, as observed in rheumatoid arthritis (RA) patients. We performed RNA sequencing and pathway analyses in mesenchymal stem cells (MSCs) isolated from transgenic TNF-expressing mice, a model of RA, to identify pathways responsible for decreased osteoblast differentiation. 53 pathways were dysregulated in MSCs from RA mice, among which expression of genes encoding NOTCH pathway members and members of the noncanonical NF-κB pathway were markedly elevated. Administration of NOTCH inhibitors to RA mice prevented bone loss and osteoblast inhibition, and CFU-fibroblasts from RA mice treated with NOTCH inhibitors formed more new bone in recipient mice with tibial defects. Overexpression of the noncanonical NF-κB subunit p52 and RELB in a murine pluripotent stem cell line increased NOTCH intracellular domain-dependent (NICD-dependent) activation of an RBPjκ reporter and levels of the transcription factor HES1. TNF promoted p52/RELB binding to NICD, which enhanced binding at the RBPjκ site within the Hes1 promoter. Furthermore, MSC-enriched cells from RA patients exhibited elevated levels of HES1, p52, and RELB. Together, these data indicate that persistent NOTCH activation in MSCs contributes to decreased osteoblast differentiation associated with RA and suggest that NOTCH inhibitors could prevent inflammation-mediated bone loss.
S76 The COPD assessment test score (CAT): a multicentre, prospective study of response to pulmonary rehabilitation
Authors: J. W. Dodd, L. Hogg, J. Nolan, H. Jefford, V. M. Lord, R. Garrod, M. I. Polkey, P. W. Jones, W. D-C Man, N. S. Hopkinson
Journal: Thorax (2010)

<h3>Background</h3> The COPD assessment test (CAT) was introduced last year.1 It is a questionnaire that contains eight questions covering domains relating to the impact of COPD symptoms. It is a self completion questionnaire and does not require scoring software. Scores of 0–10, 11–20, 21–30, 31–40 represent mild, moderate, severe or very severe clinical impact. In cross-sectional studies it has similar scaling properties to the SGRQ, so that 1 point in the CAT is equivalent to approximately 2.5 points on the SGRQ. It is not known how the CAT score performs in the context of pulmonary rehabilitation (PR). <h3>Methods</h3> We prospectively studied the introduction of the CAT score as an assessment tool in several pulmonary rehabilitation programs across London, where it was used alongside a range of other outcome measures in different programs including the SGRQ, CCQ, HAD score, MRC dyspnoea score and several different walking tests. Primary outcome was a comparison of change in CAT score against an anchor question used to assess overall response, scored 1 “I feel much better” 2 “I feel a little better”, 3 “I feel no different”, 4 “I feel a little worse”, 5 “I feel much worse”. <h3>Results</h3> Data were available for 172 COPD patients, mean(SD) age 69.6(9.3) years, FEV<sub>1</sub> 51.9(18.9)% predicted, MRC dyspnoea score 3.0(0.9), CAT score 20.0(7.5) who attended five different programs. Mean improvement in CAT score after PR was 2.8(5.8) points. In those scoring “much better” (n=108) CAT fell by 3.7(6.1) points and by 1.2(4.8) in those who felt “a little better” (n=56) (p=0.01). In those scoring 3 or 4 on the anchor question (grouped together as n=8) change in CAT was −0.6(3.5). <h3>Conclusion</h3> The CAT score improves in response to pulmonary rehabilitation and more so in those who report a greater overall improvement. Further accrual is underway to allow comparison of changes in CAT to other outcome measures.
Inhibition of Atherogenesis in BLT1-Deficient Mice Reveals a Role for LTB4 and BLT1 in Smooth Muscle Cell Recruitment
Authors: Eric A. Heller, Emerson Liu, Andrew M. Tager, Sumita Sinha, Jesse D. Roberts, Stephanie L. Koehn, Peter Libby, Elena Rabkin Aikawa, Ji Qiu Chen, Paul Huang, Mason W. Freeman, Kathryn J. Moore, Andrew D. Luster, Robert E. Gerszten
Journal: Circulation (2005)

It is known that 5-lipoxygenase and its product, leukotriene B4 (LTB4), are highly expressed in several human pathologies, including atherosclerotic plaque. LTB(4) signals primarily through its high-affinity G protein-coupled receptor BLT1, which is expressed on specific leukocyte subsets. BLT1 receptor expression and function on other atheroma-associated cell types is unknown.To directly assess the role of the LTB4-BLT1 pathway in atherogenesis, we bred BLT1(-/-) mice into the atherosclerosis-susceptible apoE(-/-) strain. Compound-deficient apoE(-/-)/Blt1(-/-) mice fed a Western-type diet had a marked reduction in plaque formation compared with apoE(-/-) controls. Immunohistochemical analysis of atherosclerotic lesions in compound-deficient mice revealed a striking decrease in smooth muscle cells (SMCs) and significant decreases in macrophages and T cells. We report here novel evidence of the expression and function of BLT1 on vascular SMCs. LTB4 triggered SMC chemotaxis, which was pertussis toxin sensitive in Blt1(+/+) SMCs and absent in Blt1(-/-) cells, suggesting that BLT1 was the dominant receptor mediating effector functions through a G protein-coupled signaling pathway. Furthermore, BLT1 colocalized with SMCs in human atherosclerotic lesions.These new findings extend the role of inducible BLT1 to nonleukocyte populations and suggest an important target for intervention to modulate the response to vascular injury.
First experience of high-intensity focused ultrasound combined with transcatheter arterial embolization as local control for hepatoblastoma
Authors: Shan Wang, Chao Yang, Jun Zhang, Xiang-ru Kong, Hui Zhu, Feng Wu, Zhibiao Wang
Journal: Hepatology (2013)

The purpose of this study was to assess the effectiveness of high-intensity focused ultrasound (HIFU) combined with transarterial chemoembolization (TACE) in treating pediatric hepatoblastoma. Twelve patients with initially unresectable hepatoblastoma were enrolled in the study. All patients received chemotherapy, TACE, and HIFU ablation. Follow-up materials were obtained in all patients. The tumor response, survival rate, and complications were analyzed. Complete ablation was achieved in 10 patients (83.3%), and the alpha-fetoprotein level was also decreased to normal in these patients. The mean follow-up time was 13.3 ± 1.8 months (range, 2-25 months). At the end of follow-up, two patients died from tumor progression, the other 10 patients were alive. One patient was found to have lung metastasis after HIFU and had an operation to remove the lesion. The median survival time was 14 months, and the 1- and 2-year survival rates were 91.7% and 83.3%, respectively. Complications included fever, transient impairment of hepatic function, and mild malformation of ribs.HIFU combined with TACE is a safe and promising method with a low rate of severe complications. As a noninvasive approach, it may provide a novel local therapy for patients with unresectable hepatoblastoma.
OC-147 Multicentre (CERT-N) audit of experience and outcomes of endoscopic balloon dilatation to treat crohn's disease strictures
Authors: M Bhalme, E Hargreaves, T Gledhill, Y Prasad, J Geraghty, S Sarkar, R Willert
Journal: Gut (2012)

<h3>Introduction</h3> Strictures are a common complication of Crohn9s disease (CD), both de novo and following surgery (Sx). While endoscopic balloon dilatation (EBD) offers a valuable alternative to Sx in managing them, there is paucity of data on factors that may influence the safety and efficacy of this technique. Our aim was to perform a multi-centre audit to determine our experience and outcomes of EBD in symptomatic CD strictures. <h3>Methods</h3> A retrospective audit across three major hospitals in Northwest England was performed on patients between 1998 and 2011. Demographics, smoking status, immunomodulation, CRP, endoscopic findings, EBD details including complications and subsequent surgery at follow-up were all recorded. Success of EBD was defined as symptomatic improvement without need for surgery at follow-up. <h3>Results</h3> Patient &amp; Disease Demographics: 71 patients (43 female; age range 17–85 years, median 47) were audited. Duration of CD was &lt;1–64 years (median 17). 45% had smoking history. CD distribution and concomitant immunomodulation was heterogenous. 58 (82%) patients had previous surgery. 46 (65%) were ileo-colonic anastomotic strictures while rest had it de novo (nine colon only, six terminal ileum, six jejunum, three duodenum, one oesophagus and one small and colon). The disease activity at anastomosis was i0–14 (30%), i1, i2–25 (55%) and i3, i4–5 (11%) while two had no record. Disease in de novo stricture was mild—5 (20%), moderate—10 (40%) and severe—7 (28%) while three had no record. The stricture length were 0.5–7 cms (median 2). CRP at first EBD was between 2 and 188 (median 5). Procedure: Maximum diameters of first and subsequent EBD were similar, 10–20 mm (median 15). 60 were performed at colonoscopy and 11 were performed at enteroscopy. 177 (range 1–11, median 2) EBD over median 8.5 months (1–84) were carried out total 84 (range 1–5, median 1) strictures. Outcomes: There were no serious complications. Success at index EBD was 31% with another 37% achieving long-term symptomatic relief from further EBDs. 18 (25%) patients needed surgery and five were lost to follow-up. Time to surgery following first EDB was 1–59 months (median 16.5). <h3>Conclusion</h3> EBD was safe and seemed fairly effective (68% cases) in achieving long-term symptom improvement and avoided the need for surgery in 75% of cases. Further large prospective trials with control groups (those going straight to surgery) are needed to evaluate effects of CD phenotypes, endoscopic techniques and patient factors to help identify those that would best achieve palliation of symptoms with EDB compared to surgery. <h3>Competing interests</h3> None declared.
IgE Antibodies to Bacteria in Patients with Bronchial Asthma
Authors: Romain Pauwels, Gerda Verschraegen, Marcel Van Der Straeten
Journal: Allergy (1980)

Bacterial respiratory infections, especially with Haemophilus influenzae and Streptococcus pneumoniae , are frequently associated with an increase of airways obstruction in patients with bronchial asthma. The possible involvement of immediate hypersensitivity in this phenomenon was studied. IgE antibodies to Haemophilus influenzae (HI) and Streptococcus pheumoniae (SPn) were investigated in the serum of 190 adult patients with bronchial asthma. The IgE antibodies were measured using a solid phase radioimmunoassay method. Living bacteria were used as solid phase. A correction of the non‐specific binding of IgE was necessary. IgE antibodies to one or both bacteria were present in 55 of the 190 patients (29%). Eighteen patients were sensitive to HI, 33 to SPn and four to both bacteria. Significantly more IgE antibodies to bacteria were found in patients with demonstrable IgE antibodies to various inhalant allergens. However, the IgE antibodies to one or both bacteria were also present in 22% of patients with no other demonstrable IgE mediated hypersensitivity. The total serum IgE level in patients with IgE antibodies to bacteria was not significantly higher than in patients without hypersensitivity to these bacteria. From these data we concluded that immediate hypersensitivity to bacteria may play a role in the infectious exacerbations of bronchial asthma.
Expansion of Cortical Interstitium Is Limited by Converting Enzyme Inhibition in Type 2 Diabetic Patients with Glomerulosclerosis
Authors: DANIEL J. CORDONNIER, NICOLE PINEL, CLAIRE BARRO, CLAIRE MAYNARD, PHILIPPE ZAOUI, SERGE HALIMI, BRUNO HURAULT DE LIGNY, YVES REZNIC, DOMINIQUE SIMON, RUDOLF W. BILOUS
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Renal interstitial expansion is now considered a useful marker of progression of several nephropathies. This study describes a multicenter, prospective, double-blind, placebo-controlled, randomized trial of the effects of Perindopril (4 mg/d) on kidney structure and function over 2 yr in 26 type 2 diabetic patients with proteinuria ranging from 70 to 4210 mg/d and relatively preserved GFR (creatinine clearance &gt;60 ml/min). All patients underwent baseline renal biopsy, but four (15%) were not randomized because of the presence of nondiabetic nephropathy. The remaining 22 were randomized (11 to Perindopril [PE], 11 to placebo [PO]), and 19 (9 PE, 10 PO) underwent follow-up biopsy at 2 yr. BP was controlled equally in both groups throughout. Proteinuria increased in PO patients (+1562 mg/d) but declined in PE patients (-156 mg/d) ( P &lt; 0.05). Morphometric analysis was performed by light microscopy using a Biocom computer. Over the 2 yr, mean cortical interstitial fractional volume identical at baseline increased significantly in PO patients (31.7 ± 5.3 versus 40.2 ± 11.1%; P = 0.001) but was unchanged in PE patients (33.8 ± 4.9 versus 34.7 ± 6.6%; P = 0.50). It is concluded that: ( 1 ) nondiabetic nephropathy is present in approximately 15% of albuminuric type 2 diabetic patients; and (2) Perindopril prevents interstitial expansion in hypertensive patients with biopsy-proven diabetic glomerulopathy. These results support a role of angiotensin II in the progression of interstitial changes in type 2 diabetic patients with nephropathy.
Influence of Ouabain on Contractile Force, Resting Tension, Ca <sup>45</sup> Entry and Tissue Ca Content in Rat Atria
Authors: GUDRUN GERSMEYER, WILLIAM C. HOLLAND
Journal: Circulation Research (1963)

As was the case with guinea pig atria, ouabain induced a small but significant increment in Ca 45 uptake and a drop of tissue Ca content in rat atria during the positive inotropic effect. In ouabain contractures, the uptake rate increased 87% to 170% and there was little increase in tissue Ca. Concentrations of the glycosides required to produce a positive inotropic effect and contracture in rat atria were 100- to 200-fold greater than those required in guinea pig atria.
Anatomy and Biology: Two Complementary Sides of Breast Cancer Prognostication
Authors: Lajos Pusztai
Journal: Journal of Clinical Oncology (2011)

represent the weighted and transformed average of two separate risk predictions from Cox models derived independently from each data set. The primary prediction end point was 10-year risk of distant recurrence, and the models were compared by using the likelihood ratio test. This statistical test is used to compare the fit of two predictionmodels,onewithallvariablesincludedandanotherwithreduced number of variables. The test is based on the likelihood ratio, which indicates how many times more likely the observed data are in one model than the other. As one might expect, by combining partially independentclinicalandmolecularvariables,theRSPChadsignificantlybetterfit,indicatinggreaterprognosticvalue,thandidRSor a clinical model including tumor size, grade, and age alone. However, the average risk of distant recurrence was not statistically significantly different for the low-, intermediate-, and high-risk cohorts defined by RS and RSPC. For example, the average risk of 10-year distant recurrence for the low-risk cohort defined by RS was 5.9% (95% CI, 4.0% to 7.8%), whereas it was 6.5% (95%CI, 4.5% to 8.5) for the low-risk group defined by RSPC. These results suggest that, although the average predicted risk by risk group is similar, the two models classify individual patients differently and the individual outcomes are more accurately predicted by the RSPC, as indicated by the significantly better fit of that model. Indeed, RSPC classified more patients as having low risk (64% v 54%) and fewer patients as having intermediate risk (18% v 27%) than did RS alone. The largest discordance in risk assignment occurred in small (1 cm), low-grade tumors for which RSPC tendedtoassignlowerriskthanRSandinlarger(3cm),high-grade
Reduction of Endotoxin and Glucan Exposures in The Louisa/Keokuk Environmental Intervention Project (LEIP) for Rural Childhood Asthma
Authors: P.S. Thorne, E.A. Chrischilles, A.K.W. Kuehl, K.M. Kelly, N. Metwali, L.M. Harris, M.E. O'Neill, A.K. Quella, R.E. Walker
Journal: Journal of Allergy and Clinical Immunology (2006)
Functional and hemodynamic adaptation to progressive renal ablation.
Authors: J M Kaufman, N J Siegel, J P Hayslett
Journal: Circulation Research (1975)

Removal of renal tissue stimulates functional and anatomical adaptation in the remaining renal parenchyma. Since recent studies have demonstrated no apparent limitation in compensatory growth following progressive surgical ablation, experiments were performed to determine the changes in glomerular filtration rate and renal blood flow. After removal of 50% of the renal mass mean nephron glomerular filtration rate increased 60%, and after ablation of 75% of the renal tissue it increased 150%. These changes paralleled the increases in renal growth under the same conditions. In comparison, mean glomerular blood flow rose 90% and 240% after 50% and 75% nephrectomy, respectively; these changes in relation to the changes in glomerular filtration rate resulted in a progressive fall in the filtration fraction. Intrarenal blood flow distribution was examined with labeled microspheres. The marked increase in renal blood flow after surgical ablation was characterized by a disproportionate rise in blood flow to the inner cortex. The present investigation, therefore, described the remarkable functional changes that occur as overall glomerular filtration rate declines and provides further insight into the mechanism responsible for maintaining water and electrolyte homeostasis after loss of functioning renal mass.
Sensitive detection of human cytomegalovirus peptide–specific cytotoxic T-lymphocyte responses by interferon-γ–enzyme-linked immunospot assay and flow cytometry in healthy individuals and in patients after allogeneic stem cell transplantation
Authors: Holger Hebart, Senay Daginik, Stefan Stevanovic, Ulrich Grigoleit, Andrea Dobler, Manuela Baur, Georg Rauser, Christian Sinzger, Gerhard Jahn, Juergen Loeffler, Lothar Kanz, Hans-Georg Rammensee, Hermann Einsele
Journal: Blood (2002)
<i>Bieträge Zur Frage nach der Beziehung Zwischen Klinischen Verlauf und Anatomischen Befund Bei Nerven und Geisteskrankheiten</i>. Bearbeitet und Herrausgegeben von Franz Nissl. Erster Band, Heft 1. (<i>Berlin: Julius Springer, 1913</i>.)
Authors: None Karpas
Journal: American Journal of Psychiatry (1914)
Global Microsatellite Content Distinguishes Humans, Primates, Animals, and Plants
Authors: C.L. Galindo, L.J. McIver, J.F. McCormick, M.A. Skinner, Y. Xie, R.A. Gelhausen, K. Ng, N.M. Kumar, H.R. Garner
Journal: Molecular Biology and Evolution (2009)

Microsatellites are highly mutable, repetitive sequences commonly used as genetic markers, but they have never been studied en masse. Using a custom microarray to measure hybridization intensities of every possible repetitive nucleotide motif from 1-mers to 6-mers, we examined 25 genomes. Here, we show that global microsatellite content varies predictably by species, as measured by array hybridization signal intensities, correlating with established taxonomic relationships, and particular motifs are characteristic of one species versus another. For instance, hominid-specific microsatellite motifs were identified despite alignment of the human reference, Celera, and Venter genomic sequences indicating substantial variation (30–50%) among individuals. Differential microsatellite motifs were mainly associated with genes involved in developmental processes, whereas those found in intergenic regions exhibited no discernible pattern. This is the first description of a method for evaluating microsatellite content to classify individual genomes.
Effect of warfarin on cell kinetics, epithelial morphology and tumour incidence in induced colorectal cancer in the rat.
Authors: N Goeting, G A Trotter, T Cooke, N Kirkham, I Taylor
Journal: Gut (1985)

The effect of low dose warfarin and high dose warfarin on epithelial cell kinetics (as determined by stathmokinetic techniques), and preneoplastic morphological changes was studied during azoxymethane induced carcinogenesis in the rat. Warfarin, at either low or high dose, had no effect on crypt cell production rate (CCPR) at any time interval whereas tumour incidence in both low dose warfarin and high dose warfarin groups was significantly reduced. Morphological changes were observed using scanning electron microscopy, which by conventional histology were shown to be adenoma precursors. In the control group the number of microadenomas increased with time after starting azoxymethane. In warfarin treated animals, the number of microadenomas also increased with time, but the actual incidence was reduced when compared with controls. These results suggest that the effects of warfarin on tumour development is unrelated to its anticoagulant effect, because increased dose did not result in greater tumour reduction. Furthermore, there was no overall change in CCPR when warfarin was administered. Warfarin may exert a specific effect, by preventing neoplastic change in cells which have undergone morphologically undetectable changes associated with early carcinogenesis.
High Anthocyanin Intake Is Associated With a Reduced Risk of Myocardial Infarction in Young and Middle-Aged Women
Authors: Aedín Cassidy, Kenneth J. Mukamal, Lydia Liu, Mary Franz, A. Heather Eliassen, Eric B. Rimm
Journal: Circulation (2013)

Our current knowledge of modifiable risk factors to prevent myocardial infarction (MI) in young and middle-aged women is limited, and the impact of diet is largely unknown. Dietary flavonoids exert potential beneficial effects on endothelial function in short-term trials; however, the relationship between habitual intake and risk of MI in women is unknown.
IL-4 gene therapy for collagen arthritis suppresses synovial IL-17 and osteoprotegerin ligand and prevents bone erosion
Authors: Erik Lubberts, Leo A.B. Joosten, Martine Chabaud, Liduine van den Bersselaar, Birgitte Oppers, Christina J.J. Coenen-de Roo, Carl D. Richards, Pierre Miossec, Wim B. van den Berg
Journal: Journal of Clinical Investigation (2000)

Bone destruction is the most difficult target in the treatment of rheumatoid arthritis (RA). Here, we report that local overexpression of IL-4, introduced by a recombinant human type 5 adenovirus vector (Ad5E1mIL-4) prevents joint damage and bone erosion in the knees of mice with collagen arthritis (CIA). No difference was noted in the course of CIA in the injected knee joints between Ad5E1mIL-4 and the control vector, but radiographic analysis revealed impressive reduction of joint erosion and more compact bone structure in the Ad5E1mIL-4 group. Although severe inflammation persisted in treated mice, Ad5E1mIL-4 prevented bone erosion and diminished tartrate-resistant acid phosphatase (TRAP) activity, indicating that local IL-4 inhibits the formation of osteoclast-like cells. Messenger RNA levels of IL-17, IL-12, and cathepsin K in the synovial tissue were suppressed, as were IL-6 and IL-12 protein production. Osteoprotegerin ligand (OPGL) expression was markedly suppressed by local IL-4, but no loss of OPG expression was noted with Ad5E1mIL-4 treatment. Finally, in in vitro studies, bone samples of patients with arthritis revealed consistent suppression by IL-4 of type I collagen breakdown. IL-4 also enhanced synthesis of type I procollagen, suggesting that it promoted tissue repair. These findings may have significant implications for the prevention of bone erosion in arthritis.