tbuckley/cabot-search huggingface dataset:
Toll-like Receptor 4 Resides in the Golgi Apparatus and Colocalizes with Internalized Lipopolysaccharide in Intestinal Epithelial Cells
Authors: Mathias W. Hornef, Teresa Frisan, Alain Vandewalle, Staffan Normark, Agneta Richter-Dahlfors
Journal: The Journal of Experimental Medicine (2002)

Toll-like receptor (TLR) 4 is mainly found on cells of the myelopoietic lineage. It recognizes lipopolysaccharide (LPS) and mediates cellular activation and production of proinflammatory cytokines. Less is known about the distribution and role of TLR4 in epithelial cells that are continuously exposed to microbes and microbial products. Here we show that the murine small intestinal epithelial cell line m-ICcl2 is highly responsive to LPS and expresses both CD14 and TLR4. Transcription and surface membrane staining for CD14 were up-regulated upon LPS exposure. Surprisingly, TLR4 immunostaining revealed a strictly cytoplasmic paranuclear distribution. This paranuclear compartment could be identified as the Golgi apparatus. LPS added to the supernatant was internalized by m-ICcl2 cells and colocalized with TLR4. Continuous exposure to LPS led to a tolerant phenotype but did not alter TLR4 expression nor cellular distribution. Thus, intestinal epithelial cells might be able to provide the initial proinflammatory signal to attract professional immune cells to the side of infection. The cytoplasmic location of TLR4, which is identical to the final location of internalized LPS, further indicates an important role of cellular internalization and cytoplasmic traffic in the process of innate immune recognition.
Five compared with six fractions per week of conventional radiotherapy of squamous-cell carcinoma of head and neck: DAHANCA 6&amp;7 randomised controlled trial
Authors: Jens Overgaard, Hanne Sand Hansen, Lena Specht, Marie Overgaard, Cai Grau, Elo Andersen, Jens Bentzen, Lars Bastholt, Olfred Hansen, Jørgen Johansen, Lisbeth Andersen, Jan F Evensen
Journal: The Lancet (2003)
Arginase Reciprocally Regulates Nitric Oxide Synthase Activity and Contributes to Endothelial Dysfunction in Aging Blood Vessels
Authors: Dan E. Berkowitz, Ron White, Dechun Li, Khalid M. Minhas, Amy Cernetich, Soonyul Kim, Sean Burke, Artin A. Shoukas, Daniel Nyhan, Hunter C. Champion, Joshua M. Hare
Journal: Circulation (2003)

Background— Although abnormal l -arginine NO signaling contributes to endothelial dysfunction in the aging cardiovascular system, the biochemical mechanisms remain controversial. l -arginine, the NO synthase (NOS) precursor, is also a substrate for arginase. We tested the hypotheses that arginase reciprocally regulates NOS by modulating l -arginine bioavailability and that arginase is upregulated in aging vasculature, contributing to depressed endothelial function. Methods and Results— Inhibition of arginase with (S)-(2-boronoethyl)- l -cysteine, HCl (BEC) produced vasodilation in aortic rings from young (Y) adult rats (maximum effect, 46.4±9.4% at 10 −5 mol/L, P &lt;0.01). Similar vasorelaxation was elicited with the additional arginase inhibitors N -hydroxy-nor- l -arginine (nor-NOHA) and difluoromethylornithine (DFMO). This effect required intact endothelium and was prevented by 1H-oxadiazole quinoxalin-1-one ( P &lt;0.05 and P &lt;0.001, respectively), a soluble guanylyl cyclase inhibitor. DFMO-elicited vasodilation was greater in old (O) compared with Y rat aortic rings (60±6% versus 39±6%, P &lt;0.05). In addition, BEC restored depressed l -arginine (10 −4 mol/L)–dependent vasorelaxant responses in O rings to those of Y. Arginase activity and expression were increased in O rings, whereas NOS activity and cyclic GMP levels were decreased. BEC and DFMO suppressed arginase activity and restored NOS activity and cyclic GMP levels in O vessels to those of Y. Conclusions— These findings demonstrate that arginase modulates NOS activity, likely by regulating intracellular l -arginine availability. Arginase upregulation contributes to endothelial dysfunction of aging and may therefore be a therapeutic target.
Non-mutualistic morality
Authors: Sonya Sachdeva, Rumen Iliev, Douglas L. Medin
Journal: Behavioral and Brain Sciences (2013)

Although mutually advantageous cooperative strategies might be an apt account of some societies, other moral systems might be needed among certain groups and contexts. In particular, in a duty-based moral system, people do not behave morally with an expectation for proportional reward, but rather, as a fulfillment of debt owed to others. In such systems, mutualistic motivations are not necessarily a key component of morality.
Glucocorticoids preferentially upregulate functional CXCR4 expression in eosinophils
Authors: Hiroyuki Nagase, Misato Miyamasu, Masao Yamaguchi, Hiroshi Kawasaki, Ken Ohta, Kazuhiko Yamamoto, Yutaka Morita, Koichi Hirai
Journal: Journal of Allergy and Clinical Immunology (2000)
Macrophage Mitochondrial Oxidative Stress Promotes Atherosclerosis and Nuclear Factor-κB–Mediated Inflammation in Macrophages
Authors: Ying Wang, Gary Z. Wang, Peter S. Rabinovitch, Ira Tabas
Journal: Circulation Research (2013)

Mitochondrial oxidative stress (mitoOS) has been shown to correlate with the progression of human atherosclerosis. However, definitive cell type-specific causation studies in vivo are lacking, and the molecular mechanisms of potential proatherogenic effects remain to be determined.Our aims were to assess the importance of macrophage mitoOS in atherogenesis and to explore the underlying molecular mechanisms.We first validated Western diet-fed Ldlr(-/-) mice as a model of human mitoOS-atherosclerosis association by showing that non-nuclear oxidative DNA damage, a marker of mitoOS in lesional macrophages, correlates with aortic root lesion development. To investigate the importance of macrophage mitoOS, we used a genetic engineering strategy in which the OS suppressor catalase was ectopically expressed in mitochondria (mCAT) in macrophages. MitoOS in lesional macrophages was successfully suppressed in these mice, and this led to a significant reduction in aortic root lesional area. The mCAT lesions had less monocyte-derived cells, less Ly6c(hi) monocyte infiltration into lesions, and lower levels of monocyte chemotactic protein-1. The decrease in lesional monocyte chemotactic protein-1 was associated with the suppression of other markers of inflammation and with decreased phosphorylation of RelA (NF-κB p65), indicating decreased activation of the proinflammatory NF-κB pathway. Using models of mitoOS in cultured macrophages, we showed that mCAT suppressed monocyte chemotactic protein-1 expression by decreasing the activation of the IκB-kinase β-RelA NF-κB pathway.MitoOS in lesional macrophages amplifies atherosclerotic lesion development by promoting NF-κB-mediated entry of monocytes and other inflammatory processes. In view of the mitoOS-atherosclerosis link in human atheromata, these findings reveal a potentially new therapeutic target to prevent the progression of atherosclerosis.
A neural factor involved in increase of the glycogen phosphorylase activity after coronary ligation in both ischemic and nonischemic areas of the dog heart.
Authors: K Sakai, Y Abiko
Journal: Circulation Research (1982)

We performed experiments to determine whether or not extracardiac factors are involved in the increase of the glycogen phosphorylase activity after coronary artery ligation in dog hearts. A branch of the left anterior descending coronary artery (LAD) was ligated for 1.5 minutes. The glycogen phosphorylase activity was determined in the endo- and epicardial layers. LAD ligation significantly increased the glycogen phosphorylase activity in both LAD (ischemic) and circumflex (nonischemic) areas. Pretreatment with reserpine (1 mg/kg, im, 24 hours before experiments) or hexamethonium (3 mg/kg, iv) prevented the LAD ligation-induced increase in the glycogen phosphorylase activity, but adrenalectomy did not. In the heart-lung preparation and stellectomized dogs, LAD ligation did not increase the glycogen phosphorylase activity in both ischemic and nonischemic areas. Changes in the glycogen phosphorylase activity in the endocardial layers were not essentially different from those in the epicardial layers. In other dogs, metabolic intermediates and ST segment of the surface electrocardiogram were measured. LAD ligation significantly decreased the tissue level of creatine phosphate and increased that of lactate in the ischemic but not in the nonischemic area. An elevation of ST segment occurred only in the ischemic area. Thus ischemic and nonischemic areas were confirmed. The ATP level, however, did not change in any of the ischemic and nonischemic areas. It is suggested that LAD ligation increases the glycogen phosphorylase activity in both ischemic and nonischemic areas probably by an increase in the efferent cardiac sympathetic nerve activity.
An Address on PELVIC SEPSIS: GIVEN TO THE SOUTH-WEST ESSEX DIVISION OF THE BRITISH MEDICAL ASSOCIATION
Authors: A. L. McIlroy
Journal: BMJ (1929)

PELVIC SEPSIS iS onle of tlle most importanit subjects in medicinie.It is a daniger' to life.It is tilhe caise of ill healtim on the part of mnany women.It iiiter fere s with replro(luctive fuinictioni and leads to more domefstic a nxietv and coiijugal infelicity thail almost Iny other disease.'What are the natuir-al defences of the pelvic organs againist inifection?Although the reproductive organs con- sist of a series of canals whicih )oteitially lead fromi tile open air to the peritoneal cavity, the structure of these passages is so arranged as to ensiure almost complete occlusioni.The labia close over the vaginal entr anice, and the.walls of the latter lie in antero-posterior appositioll.The cervical ca'inal -is narrow an(d sealed by muctus.Tile secretion of the ulterine glands, the cilia, the muiscular conitr-actioIns, all prevent the ascent of bacteria.The tortiuous conidition of -the Fallopian tube is an important element in the closure of its lumen.The vagina colnitains time bacillus of D6derlein, which is a powerful ageent against the elntrance of inifection.When this bacillius is presenit patholo[gical bacteria are as a ruile absent.Dr. ChdrlotteHoulitton, in the Obstetr-ical Unit at the Royal Free Hospital, made a very comprehensive investigation of the vaginal and cervical dischaxge during pregnanicy.If the lacilluts raqinalis i was present ill ilimbers pluel)peral sepsis was less likely to ocecir than in those cases whilere the bacilli were scanty or absent.Various otliler research wor'ker's hlave also found that str'eptococci are so fre- qlmenty lpresenlt in tile vagina as to wiarranit the assuimption that these bacteria are protective in funetion.With all these methods of defence, how-does infectioni gaini ani entrance?Mainlv by means of the exer cise of the reproductive fiunction.In vil'gins pelvic; sepsis is rare, apart from toxic intestinal conditionis or tuberculolus
Familial Mediterranean fever (FMF) and beyond: a new horizon. Fourth International Congress on the Systemic Autoinflammatory Diseases held in Bethesda, USA, 6-10 November 2005
Authors: S Ozen
Journal: Annals of the Rheumatic Diseases (2005)

Autoinflammatory diseases are characterised by seemingly unprovoked inflammation. They can be categorised as: hereditary (monogenic) autoinflammatory diseases, complex (polygenic/multifactorial) autoinflammatory diseases, and diseases where the course is affected by mutations in the defined autoinflammatory disease genes. Identification of the inflammatory pathways involved has opened up new areas of research which have implications for the treatment of these disorders and the pathogenesis of common inflammatory diseases.
Treatment of Localized Nonorbital, Nonparameningeal Head and Neck Rhabdomyosarcoma: Lessons Learned From Intergroup Rhabdomyosarcoma Studies III and IV
Authors: Alberto S. Pappo, Jane L. Meza, Sarah S. Donaldson, Moody D. Wharam, Eugene S. Wiener, Stephen J. Qualman, Harold M. Maurer, William M. Crist
Journal: Journal of Clinical Oncology (2003)

Purpose: The characteristics and clinical outcomes of children and adolescents with localized nonorbital, nonparameningeal head and neck rhabdomyosarcoma (RMS) treated on national protocols from the Intergroup Rhabdomyosarcoma Group are reported. Patients and Methods: We conducted a retrospective review of 164 children and adolescents enrolled in the third and fourth Intergroup Rhabdomyosarcoma Studies. Variables analyzed included age, sex, primary tumor site, histologic subtype, clinical group, therapy, site and rate of treatment failure, and time to initial recurrence. Results: Localized nonorbital, nonparameningeal RMS accounted for 9% of all cases of RMS. The median age at diagnosis was 5 years; the median follow-up was 6.6 years. Estimated 5-year failure-free survival (FFS) and survival (S) rates were 76% (95% CI, 69% to 83%) and 83% (95% CI, 77% to 89%), respectively. In multivariate analysis, patients with clinically involved regional nodes (N1) had worse FFS (P = .02). For patients with embryonal tumors, FFS was significantly improved, especially among patients with Group I/II without nodal disease clinical Group I, II N0. For patients with alveolar/undifferentiated histology, FFS was significantly worse in children under the age of 1 year. Actuarial estimates of recurrences at 15 years were local (19%), regional (5%), and distant (9%). Conclusion: More than 80% of patients with RMS of the head and neck are cured of their disease using surgery and vincristine, dactinomycin ± cyclophosphamide with or without radiotherapy. Our results indicate that early, limited exposure to cyclophosphamide might reduce recurrence in low-risk embryonal patients and that reduced dosages might achieve comparable results with improved toxicity profiles. These hypotheses will be tested in the next generation of trials from the Soft Tissue Committee of the Children’s Oncology Group.
Aerosol deposition in the human lung following administration from a microprocessor controlled pressurised metered dose inhaler.
Authors: S J Farr, A M Rowe, R Rubsamen, G Taylor
Journal: Thorax (1995)

BACKGROUND--Gamma scintigraphy was employed to assess the deposition of aerosols emitted from a pressurised metered dose inhaler (MDI) contained in a microprocessor controlled device (SmartMist), a system which analyses an inspiratory flow profile and automatically actuates the MDI when predefined conditions of flow rate and cumulative inspired volume coincide. METHODS--Micronised salbutamol particles contained in a commercial MDI (Ventolin) were labelled with 99m-technetium using a method validated by the determination of (1) aerosol size characteristics of the drug and radiotracer following actuation into an eight stage cascade impactor and (2) shot potencies of these non-volatile components as a function of actuation number. Using nine healthy volunteers in a randomised factorial interaction design the effect of inspiratory flow rate (slow, 30 l/min; medium, 90 l/min; fast, 270 l/min) combined with cumulative inspired volume (early, 300 ml; late, 3000 ml) was determined on total and regional aerosol lung deposition using the technique of gamma scintigraphy. RESULTS--The SmartMist firing at the medium/early setting (medium flow and early in the cumulative inspired volume) resulted in the highest lung deposition at 18.6 (1.42)%. The slow/early setting gave the second highest deposition at 14.1 (2.06)% with the fast/late setting resulting in the lowest (7.6 (1.15)%). Peripheral lung deposition obtained for the medium/early (9.1 (0.9)%) and slow/early (7.5 (1.06)%) settings were equivalent but higher than those obtained with the other treatments. This reflected the lower total lung deposition at these other settings as no difference in regional deposition, expressed as a volume corrected central zone:peripheral zone ratio, was apparent for all modes of inhalation studied. CONCLUSIONS--The SmartMist device allowed reproducible actuation of an MDI at a preprogrammed point during inspiration. The extent of aerosol deposition in the lung is affected by a change in firing point and is promoted by an inhaled flow rate of up to 90 l/min-that is, the slow and medium setting used in these studies.
Sirolimus- vs Paclitaxel-Eluting Stents in De Novo Coronary Artery Lesions
Authors: Marie-Claude Morice, Antonio Colombo, Bernhard Meier, Patrick Serruys, Corrado Tamburino, Giulio Guagliumi, Eduardo Sousa, Hans-Peter Stoll, for the REALITY Trial Investigators
Journal: JAMA (2006)

Compared with bare metal stents, sirolimus-eluting and paclitaxel-eluting stents have been shown to markedly improve angiographic and clinical outcomes after percutaneous coronary revascularization, but their performance in the treatment of de novo coronary lesions has not been compared in a prospective multicenter study.To compare the safety and efficacy of sirolimus-eluting vs paclitaxel-eluting coronary stents.Prospective, randomized comparative trial (the REALITY trial) conducted between August 2003 and February 2004, with angiographic follow-up at 8 months and clinical follow-up at 12 months.Ninety hospitals in Europe, Latin America, and Asia.A total of 1386 patients (mean age, 62.6 years; 73.1% men; 28.0% with diabetes) with angina pectoris and 1 or 2 de novo lesions (2.25-3.00 mm in diameter) in native coronary arteries.Patients were randomly assigned in a 1:1 ratio to receive a sirolimus-eluting stent (n = 701) or a paclitaxel-eluting stent (n = 685).The primary end point was in-lesion binary restenosis (presence of a more than 50% luminal-diameter stenosis) at 8 months. Secondary end points included 1-year rates of target lesion and vessel revascularization and a composite end point of cardiac death, Q-wave or non-Q-wave myocardial infarction, coronary artery bypass graft surgery, or repeat target lesion revascularization.In-lesion binary restenosis at 8 months occurred in 86 patients (9.6%) with a sirolimus-eluting stent vs 95 (11.1%) with a paclitaxel-eluting stent (relative risk [RR], 0.84; 95% confidence interval [CI], 0.61-1.17; P = .31). For sirolimus- vs paclitaxel-eluting stents, respectively, the mean (SD) in-stent late loss was 0.09 (0.43) mm vs 0.31 (0.44) mm (difference, -0.22 mm; 95% CI, -0.26 to -0.18 mm; P<.001), mean (SD) in-stent diameter stenosis was 23.1% (16.6%) vs 26.7% (15.8%) (difference, -3.60%; 95% CI, -5.12% to -2.08%; P<.001), and the number of major adverse cardiac events at 1 year was 73 (10.7%) vs 76 (11.4%) (RR, 0.94; 95% CI, 0.69-1.27; P = .73).In this trial comparing sirolimus- and paclitaxel-eluting coronary stents, there were no differences in the rates of binary restenosis or major adverse cardiac events.ClinicalTrials.gov Identifier: NCT00235092.
p2y5/LPA6 attenuates LPA1-mediated VE-cadherin translocation and cell–cell dissociation through G12/13 protein–Src–Rap1
Authors: Takao Kimura, Chihiro Mogi, Koichi Sato, Hideaki Tomura, Hideo Ohta, Doon-Soon Im, Atsushi Kuwabara, Hitoshi Kurose, Masami Murakami, Fumikazu Okajima
Journal: Cardiovascular Research (2011)

We investigated the mechanisms of action of lysophosphatidic acid (LPA) to regulate vascular endothelial (VE)-cadherin dynamics and cell–cell contact. While a low concentration of LPA stimulated VE-cadherin internalization and subsequent cell–cell dissociation, a high concentration of LPA masked the disruptive actions on VE-cadherin and protected the barrier function in human vascular endothelial cells. Knockdown experiments of major LPA receptor subtypes, i.e. LPA1 and p2y5 (also termed LPA6), with their specific small interfering RNAs, showed that LPA1 and LPA6 mediate the LPA-induced disruptive and protective actions on barrier integrity, respectively. LPA6-mediated tube formation, reflecting stabilization of barrier integrity, was confirmed by in vitro angiogenesis assay. The LPA1-mediated disruptive actions were inhibited by pertussis toxin, dominant-negative Rac1, and inhibitors for c-Jun NH2-terminal kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), but not by dominant-negative RhoA. In contrast, the LPA6-mediated protective actions were associated with activation of Src and Rap1 and attenuated by abrogation of their activities. Further characterization showed that Rap1 is located downstream of Src and dependent on C3G, a Rap1 guanine nucleotide exchange factor. Finally, an LPA antagonist significantly inhibited lactic acid-induced limb lesions in vivo, which may be attributed to dysfunction of endothelial cells. LPA induced disruption and protection of VE-cadherin integrity through LPA1–Gi protein–Rac1–JNK/p38MAPK and LPA6–G12/13 protein–Src–C3G–Rap1 pathways, respectively.
Human Telomere Reverse Transcriptase Expression Predicts Progression and Survival in Pediatric Intracranial Ependymoma
Authors: Uri Tabori, Jing Ma, Michael Carter, Maria Zielenska, James Rutka, Eric Bouffet, Ute Bartels, David Malkin, Cynthia Hawkins
Journal: Journal of Clinical Oncology (2006)

Pediatric intracranial ependymomas are a heterogeneous group of neoplasms with unpredictable clinical and biologic behavior. As part of ongoing studies to identify potential biologic and therapeutic markers, we analyzed the role of human telomere reverse transcriptase (hTERT; the catalytic subunit of telomerase) expression as a prognostic marker for this disease.Primary intracranial ependymomas that were resected at our institution between 1986 and 2004 were identified through the pathology and oncology databases. A tissue array was constructed from the patient samples and hTERT expression was evaluated by immunohistochemistry. Twenty-one samples were also analyzed for telomerase activity (telomerase repeat amplification protocol assay).Eighty-seven tumors from 65 patients were analyzed. Five-year progression-free survival was 57% (SEM, 12%) and 21% (SEM, 8%) for hTERT-negative and hTERT-positive tumors, respectively (P = .002). Five-year overall survival was 84% (SEM, 7%) and 41% (SEM, 7%) for hTERT-negative and hTERT-positive tumors, respectively (P = .001). There was good correlation between telomerase activity and hTERT expression (kappa = 0.637). Multivariate analysis revealed hTERT expression to be the single most important predictor of survival of all known pathologic, clinical, and treatment factors (hazard ratio, 60.4; 95% CI, 6.4 to 561). All four patients with hTERT-negative tumors at relapse are still alive, with median follow-up of 11.2 years.In this study, hTERT expression was the strongest predictor of outcome and was independent of other clinical and pathologic prognostic markers. It represents a simple and reliable biologic prognostic factor for intracranial ependymomas. These results should be confirmed in larger prospective trials.
Pleural effusion: laboratory tests in 300 cases.
Authors: A Hirsch, P Ruffie, M Nebut, J Bignon, J Chretien
Journal: Thorax (1979)

The cause of pleural effusion was studied in 300 consecutive patients by clinical examination and laboratory tests. The three most common causes were found to be cancer 117 cases (metastatic 65, bronchogenic 34, mesothelioma 10, lymphoma 7, other 1); tuberculous infection 53; and bacterial infection 38. The cause was not found in 62 patients. Cancer diagnosis was established by cytological examination of pleural fluid (63), closed pleural biopsy (37), and open pleural biopsy (11). Tuberculosis was diagnosed by culture of pleural fluid (12), closed pleural biopsy (38), and open pleural biopsy (3). In cases of empyema 12 Gram-positive and two Gram-negative cocci and two anaerobes were identified. The various causes and the usefulness of the different investigative procedures are discussed, and the data evaluated in the light of current knowledge about mechanisms of transfer through the pleural space.