tbuckley/cabot-search huggingface dataset:
Communication between myocytes and fibroblasts in cardiac remodeling in angiotensin chimeric mice
Authors: Taiji Matsusaka, Hideyuki Katori, Tadashi Inagami, Agnes Fogo, Iekuni Ichikawa
Journal: Journal of Clinical Investigation (1999)

To characterize the mode of action of angiotensin II (Ang II) in cardiac remodeling, we generated chimeric mice that are made of both homozygous Ang II receptor type 1A gene (Agtr1a) null mutant cells and Agtr1a intact cells expressing the lacZ gene (ROSA26). Both Agtr1a null and intact myocytes and interstitial cells independently form areas that are randomly distributed throughout the heart. The distribution of ROSA26 cardiomyocytes overlaps completely with that of Ang II binding, indicating that the majority of Ang II receptors reside on cardiomyocytes. When Ang II (1 ng/g body weight/min) was infused for 2 weeks, mice developed mild to moderate hypertension. The proliferating cardiac fibroblasts identified by bromodeoxyuridine staining were present predominantly in the areas surrounded by Agtr1a intact cardiomyocytes. When control chimeric mice made of wild-type cells and ROSA26 cells (i.e., both carrying intact Agtr1a) were infused with Ang II, fibroblast proliferation was found equally in these cardiomyocyte types. When compared with Agtr1a null mutant chimeras, the control chimeras had more extensive cardiac fibrosis, most prominently in perivascular regions. Therefore, in response to Ang II, cardiac fibroblasts proliferate through both the local and systemic action of Ang II. Importantly, the former is determined by the Ang II receptor of neighboring cardiomyocytes, indicating that a communication between myocytes and fibroblasts plays an important role during Ang II-dependent cardiac remodeling.
Long-term sedation in intensive care unit: a randomized comparison between inhaled sevoflurane and intravenous propofol or midazolam
Authors: Malcie Mesnil, Xavier Capdevila, Sophie Bringuier, Pierre-Olivier Trine, Yoan Falquet, Jonathan Charbit, Jean-Paul Roustan, Gerald Chanques, Samir Jaber
Journal: Intensive Care Medicine (2011)
Marking a path to transplant tolerance
Authors: Vicki Seyfert Margolis, Laurence A. Turka
Journal: Journal of Clinical Investigation (2008)

Long-term allograft survival requires lifelong immunosuppression, which comes with serious side effects. Inducing immune tolerance to the transplant would enable immunosuppression withdrawal and revolutionize the quality of life of transplant recipients. In this issue of the JCI, Martínez-Llordella et al. identify a profile of biomarkers that predict tolerance in liver transplant recipients (see the related article beginning on page 2845). These findings translate into a new means for prospectively selecting liver transplant patients who would benefit from immunosuppression withdrawal and ultimately may guide development of tolerogenic therapies that allow for allograft acceptance without the use of long-term immunosuppression.
Breast Cancer Metastasis Suppressor 1 Inhibits Gene Expression by Targeting Nuclear Factor-κB Activity
Authors: Muzaffer Cicek, Ryuichi Fukuyama, Danny R. Welch, Nywana Sizemore, Graham Casey
Journal: Cancer Research (2005)

Abstract Breast cancer metastasis suppressor 1 (BRMS1) functions as a metastasis suppressor gene in breast cancer and melanoma cell lines, but the mechanism of BRMS1 suppression remains unclear. We determined that BRMS1 expression was inversely correlated with that of urokinase-type plasminogen activator (uPA), a prometastatic gene that is regulated at least in part by nuclear factor-κB (NF-κB). To further investigate the role of NF-κB in BRMS1-regulated gene expression, we examined NF-κB binding activity and found an inverse correlation between BRMS1 expression and NF-κB binding activity in MDA-MB-231 breast cancer and C8161.9 melanoma cells stably expressing BRMS1. In contrast, BRMS1 expression had no effect on activation of the activator protein-1 transcription factor. Further, we showed that suppression of both constitutive and tumor necrosis factor-α–induced NF-κB activation by BRMS1 may be due to inhibition of IκBα phosphorylation and degradation. To examine the relationship between BRMS1 and uPA expression in primary breast tumors, we screened a breast cancer dot blot array of normalized cDNA from 50 breast tumors and corresponding normal breast tissues. There was a significant reduction in BRMS1 mRNA expression in breast tumors compared with matched normal breast tissues (paired t test, P &amp;lt; 0.0001) and a general inverse correlation with uPA gene expression (P &amp;lt; 0.01). These results suggest that at least one of the underlying mechanisms of BRMS1-dependent suppression of tumor metastasis includes inhibition of NF-κB activity and subsequent suppression of uPA expression in breast cancer and melanoma cells.
Subclinical Atherosclerosis Measures for Cardiovascular Prediction in CKD
Authors: Kunihiro Matsushita, Yingying Sang, Shoshana H. Ballew, Michael Shlipak, Ronit Katz, Sylvia E. Rosas, Carmen A. Peralta, Mark Woodward, Holly J. Kramer, David R. Jacobs, Mark J. Sarnak, Josef Coresh
Journal: Journal of the American Society of Nephrology (2014)

Whether inclusion of the coronary artery calcium score improves cardiovascular risk prediction in individuals with CKD, a population with unique calcium-phosphate homeostasis, is unknown. Among 6553 participants ages 45-84 years without prior cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis, coronary artery calcium score was assessed for cardiovascular risk prediction beyond the Framingham predictors in those with (n=1284) and without CKD and contrasted with carotid intima-media thickness and ankle-brachial index (two other measures of subclinical atherosclerosis). During a median follow-up of 8.4 years, 650 cardiovascular events (coronary heart disease, stroke, heart failure, and peripheral artery disease) occurred (236 events in subjects with CKD). In Cox proportional hazards models adjusted for Framingham predictors, each subclinical measure was independently associated with cardiovascular outcomes, with larger adjusted hazard ratios (HRs; per 1 SD) for coronary artery calcium score than carotid intima-media thickness or ankle-brachial index in subjects without and with CKD (HR, 1.69; 95% confidence interval [95% CI], 1.45 to 1.97 versus HR, 1.12; 95% CI, 1.00 to 1.25 and HR, 1.20; 95% CI, 1.08 to 1.32, respectively). Compared with inclusion of carotid intima-media thickness or ankle-brachial index, inclusion of the coronary artery calcium score led to greater increases in C statistic for predicting cardiovascular disease and net reclassification improvement. Coronary artery calcium score performed best for the prediction of coronary heart disease and heart failure, regardless of CKD status. In conclusion, each measure improved cardiovascular risk prediction in subjects with CKD, with the greatest improvement observed with coronary artery calcium score.
Atherosclerosis and proteinase activation
Authors: C DOLLERY, P LIBBY
Journal: Cardiovascular Research (2005)

Rapidly accumulating evidence points to the matrix metalloproteinases (MMPs) as major molecular mediators of arterial diseases. Findings from human pathological specimens, animals, and cell and molecular biology implicate matrix metalloproteinases in all stages of atherosclerosis including lesion initiation and progression and ultimately in plaque complication and triggering of thrombosis. The complex interactions within the proteolytic cascade allow multiple levels of control over these functions. This review weighs the evidence for the role of MMPs in arterial biology with particular reference to their activation in the atherosclerotic plaque.
Relevance of pharmacokinetics and pharmacodynamics of inhaled corticosteroids to asthma
Authors: H. Derendorf, R. Nave, A. Drollmann, F. Cerasoli, W. Wurst
Journal: European Respiratory Journal (2006)

The pharmacokinetic and pharmacodynamic effects of inhaled corticosteroids (ICS) have shaped the efficacy and safety of these agents in the treatment of asthma. Important pharmacokinetic and pharmacodynamic characteristics that can enhance the efficacy of ICS include small particle size, high glucocorticoid-receptor-binding affinity, long pulmonary residence time and lipid conjugation. These characteristics can increase or prolong the anti-inflammatory effects of an ICS. Important pharmacokinetic characteristics that can enhance the safety of ICS include on-site activation in the lung, low oropharyngeal exposure, negligible oral bioavailability, high protein-binding and rapid systemic clearance. The degree of oropharyngeal exposure is relevant to local side-effects, such as oropharyngeal candidiasis, dysphonia and coughing. Pharmacokinetic properties that influence the degree of systemic exposure are relevant to the pharmacodynamic effect of ICS-induced hypothalamic–pituitary–adrenal axis suppression and cortisol suppression, an indicator of potential long-term systemic side-effects, such as reduced growth velocity and bone density, fractures, and skin bruising and thinning. Therefore, significant differences in the pharmacokinetic and pharmacodynamic characteristics of the currently available inhaled corticosteroids warrant careful consideration when used in clinical practice as they may result in differences in efficacy and local and systemic safety profiles.
Review of David Novak,<i>The Sanctity of Human Life</i><sup>1</sup>
Authors: Christiana Z. Peppard
Journal: The American Journal of Bioethics (2008)

"Review of David Novak, The Sanctity of Human Life 1 ." , 8(11), pp. 51–52 Notes 1. Washington, D.C.: Georgetown University Press, 2007. 186 pp. $34.95 hardcover.
Chemotherapeutic Sensitivity of Testicular Germ Cell Tumors Under Hypoxic Conditions Is Negatively Regulated by SENP1-Controlled Sumoylation of OCT4
Authors: Yu-Chih Wu, Thai-Yen Ling, Shing-Hwa Lu, Hung-Chih Kuo, Hong-Nerng Ho, Shauh-Der Yeh, Chia-Ning Shen, Yen-Hua Huang
Journal: Cancer Research (2012)

Testicular germ cell tumors (TGCT) generally respond well to chemotherapy, but tumors that express low levels of the transcription factor OCT4 are associated with chemoresistance and poor prognosis. Hypoxia is known to induce drug resistance in TGCTs; however, the mechanistic basis for reduced expression of OCT4 and drug resistance is unclear. Here we show that hypoxia reduces OCT4 levels and increases the resistance of embryonal carcinoma (EC) cells to cisplatin and bleomycin. Furthermore, we show that the loss of OCT4 expression under hypoxia can be triggered by sumoylation, which was regulated by SUMO1 and the SUMO1 peptidase SENP1. Under hypoxic conditions, overexpression of SUMO1gg (the active form of SUMO1) not only increased the level of sumoylated OCT4 (Su-OCT4), but also decreased the stability of OCT4 protein. In addition, overexpression of SENP1 reduced the Su-OCT4 level induced by SUMO1gg overexpression, thereby maintaining OCT4 levels and enhancing chemosensitivity. Mechanistic investigations revealed that OCT4 sumoylation occurred at K123, as overexpression of an OCT4-K123R mutant effectively reduced the level of Su-OCT4 under hypoxic conditions. Taken together, our results showed that hypoxia reduces OCT4 expression levels in ECs to increase drug resistance and that these effects could be countered to ablate the suppressive effects of hypoxia on chemosensitivity. Our findings also highlight SENP1 as a potential therapeutic target for drug resistant TGCTs.
SIMULTANEOUS LIGATURE OF ARTERIAL AND VENOUS TRUNKS IN WAR SURGERY
Authors: E. M. Cowell
Journal: BMJ (1917)

SIMULTANEOUS LIGATUIRE OF ARTERIES AND VEINS.[ TE BRlsT 577 M A'y 5, 119171 ruF.~~~~~~~~~~~~~~~~~~~~~~MDICALJORA 57 the blood after paratlhyroidectoiny from 400 per.cenLt.to 1,200 per cent.It wras thoughst thlat the action of guanidin in cauising tremors of the excised muscle of the froa mihlt be used as a test for its presence 'in the blood after Darathyroidectomy.Wislhart stuldied the action of tlle blood of para- thyroidectomized animals uponi sucil muscles.His ex- periments shiow tlhat wlile the blood of normal anim-als fails to cause any twitchliing or any alteration in the forii of contra^,tion of the mnuscle, in several cases twitching, and. in -a greater nLumber prolongation of contraction, occurred.H. The Metaboalism after Paraflyroidectomiqy anii the Admin istrahtim of Gua,nidin.A series-of-experimeints carried out by Burns slhows tlle similarity of the ehanges in the distribution of nitrogen in thiese two-coniditions.-
Electrophysiological effects of ajmaline in isolated cardiac tissue
Authors: K. OBAYASHI, W. J. MANDEL
Journal: Cardiovascular Research (1976)

Journal Article Electrophysiological effects of ajmaline in isolated cardiac tissue Get access KANJI OBAYASHI, KANJI OBAYASHI From the Department of Cardiology, Cedars-Sinai Medical Center and The Department of Medicine, University of California, Los Angeles, California 90029, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar WILLIAM J. MANDEL WILLIAM J. MANDEL 2 From the Department of Cardiology, Cedars-Sinai Medical Center and The Department of Medicine, University of California, Los Angeles, California 90029, USA 2Milly Factor Clinical Investigator of the Western Cardiac Foundation. Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 10, Issue 1, January 1976, Pages 20–24, https://doi.org/10.1093/cvr/10.1.20 Published: 01 January 1976
Obstructive sleep apnoea and risk of stroke and death
Authors: Y Wedatilake
Journal: Thorax (2006)

▴ Yaggi HK, Concato J, Kernan WN, et al . Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med2005;353:2034–41 [OpenUrl][1][CrossRef][2][PubMed][3][Web of Science][4] The effect of obstructive sleep apnoea (OSA) as a risk factor for stroke and death was investigated in 1022 referrals to the Yale Center for Sleep Medicine. 68% (697 subjects) had OSA as defined by an apnoea-hypopnoea index (AHI) of more than … [1]: {openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.issn%253D0028-4793%26rft.aulast%253DYaggi%26rft.auinit1%253DH.%2BK.%26rft.volume%253D353%26rft.issue%253D19%26rft.spage%253D2034%26rft.epage%253D2041%26rft.atitle%253DObstructive%2BSleep%2BApnea%2Bas%2Ba%2BRisk%2BFactor%2Bfor%2BStroke%2Band%2BDeath.%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa043104%26rft_id%253Dinfo%253Apmid%252F16282178%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [2]: /lookup/external-ref?access_num=10.1056/NEJMoa043104&link_type=DOI [3]: /lookup/external-ref?access_num=16282178&link_type=MED&atom=%2Fthoraxjnl%2F61%2F2%2F133.atom [4]: /lookup/external-ref?access_num=000233119600008&link_type=ISI
Transcriptional Repression of Telomerase RNA Gene Expression by c-Jun-NH2-Kinase and Sp1/Sp3
Authors: Alan E. Bilsland, Katrina Stevenson, Stuart Atkinson, Walter Kolch, W. Nicol Keith
Journal: Cancer Research (2006)

Abstract Telomerase is essential for immortalization of most human cancer cells. Expression of the core telomerase RNA (hTR) and reverse transcriptase (hTERT) subunits is mainly regulated by transcription. However, hTR transcriptional regulation remains poorly understood. We previously showed that the core hTR promoter is activated by Sp1 and is repressed by Sp3. Here, we show that the mitogen-activated protein kinase kinase kinase 1 (MEKK1)/c-Jun-NH2-kinase (JNK) pathway represses hTR expression by a mechanism that involves Sp1 and Sp3. Promoter activity was induced by the JNK inhibitor SP600125 and was repressed by activated MEKK1. Repression by MEKK1 was blocked by SP600125 or enhanced by coexpression of wild-type but not phosphoacceptor mutated JNK. SP600125 treatment also increased levels of endogenous hTR. Mutations in the hTR promoter Sp1/Sp3 binding sites attenuated SP600125-mediated promoter induction, whereas coexpression of MEKK1 with Sp3 enhanced hTR promoter repression. Chromatin immunoprecipitation showed that levels of immunoreactive Sp1 associated with the hTR promoter were low in comparison with Sp3 in control cells but increased after JNK inhibition with a reciprocal decrease in Sp3 levels. No corresponding changes in Sp1/Sp3 protein levels were detected. Thus, JNK represses hTR promoter activity and expression, apparently by enhancing repression through Sp3. (Cancer Res 2006; 66(3): 1363-70)
β-Score
Authors: Edmond A. Ryan, Breay W. Paty, Peter A. Senior, Jonathan R.T. Lakey, David Bigam, A.M. James Shapiro
Journal: Diabetes Care (2005)

Success after islet transplantation can be defined in terms of insulin independence, C-peptide secretion, or glycemic control. These measures are interdependent and all need to be considered in evaluating beta-cell function after islet transplantation. For the current study, a composite beta-score was developed that provides an integrated measure of beta-cell function success after islet transplantation.The proposed scoring system gave 2 points each for normal fasting glucose, HbA(1c), stimulated C-peptide, and absence of insulin or oral hypoglycemic agent use. No points were awarded if the fasting glucose was in the diabetic range, the HbA(1c) was >6.9%, C-peptide secretion was absent on stimulation, or daily insulin use was in excess of 0.24 units/kg. One point was given for intermediate values. The score ranged from 0 to 8 and was correlated with the glucose value 90 min after a standard mixed meal challenge (n = 218) in 57 subjects before and after islet transplantation. The score was also used to follow subjects for up to 5 years after islet transplantation.The beta-score correlated well with the plasma glucose level 90 min after a mixed meal challenge (r = -0.849, P < 0.001). On follow-up, the beta-score rose after the first transplant and was maintained up to 5 years, demonstrating continuing function of the transplanted beta-cells.The beta-score provides a simple clinical scoring system that encompasses glycemic control, diabetes therapy, and endogenous insulin secretion that correlates well with physiological measures of beta-cell function. On this basis, it is suitable as an overall measure of beta-cell transplant function. The beta-score gives an integrated measure of beta-cell function as a continuum that may be more useful than simply assessing the presence or absence of insulin independence.
Epidemiology of Sepsis Syndrome in 8 Academic Medical Centers
Authors: K E Sands, D W Bates, P N Lanken, P S Graman, P L Hibberd, K L Kahn, J Parsonnet, R Panzer, E J Orav, D R Snydman, E Black, J S Schwartz, R Moore, B L Johnson, R Platt
Journal: JAMA (1997)

Sepsis syndrome is a leading cause of mortality in hospitalized patients. However, few studies have described the epidemiology of sepsis syndrome in a hospitalwide population.To describe the epidemiology of sepsis syndrome in the tertiary care hospital setting.Prospective, multi-institutional, observational study including 5-month follow-up.Eight academic tertiary care centers.Each center monitored a weighted random sample of intensive care unit (ICU) patients, non-ICU patients who had blood cultures drawn, and all patients who received a novel therapeutic agent or who died in an emergency department or ICU. Sepsis syndrome was defined as the presence of either a positive blood culture or the combination of fever, tachypnea, tachycardia, clinically suspected infection, and any 1 of 7 confirmatory criteria. Estimates of total cases expected annually were extrapolated from the number of cases, the period of observation, and the sampling fraction.From January 4, 1993, to April 2, 1994, 12759 patients were monitored and 1342 episodes of sepsis syndrome were documented. The extrapolated, weighted estimate of hospitalwide incidence (mean+/-95% confidence limit) of sepsis syndrome was 2.0+/-0.16 cases per 100 admissions, or 2.8+/-0.17 per 1000 patient-days. The unadjusted attack rate for sepsis syndrome between individual centers differed by as much as 3-fold, but after adjustment for institutional differences in organ transplant populations, variation from the expected number of cases was reduced to 2-fold and was not statistically significant overall. Patients in ICUs accounted for 59% of total extrapolated cases, non-ICU patients with positive blood cultures for 11%, and non-ICU patients with negative blood cultures for 30%. Septic shock was present at onset of sepsis syndrome in 25% of patients. Bloodstream infection was documented in 28%, with gram-positive organisms being the most frequent isolates. Mortality was 34% at 28 days and 45% at 5 months.Sepsis syndrome is common in academic hospitals, although the overall rates vary considerably with the patient population. A substantial fraction of cases occur outside ICUs. An understanding of the hospitalwide epidemiology of sepsis syndrome is vital for rational planning and treatment of hospitalized patients with sepsis syndrome, especially as new and expensive therapeutic agents become available.
Monoclonal IgM rheumatoid factors derived from arthritic MRL/Mp-lpr/lpr mice.
Authors: A N Theofilopoulos, R S Balderas, L Hang, F J Dixon
Journal: The Journal of Experimental Medicine (1983)

MRL/lpr/lpr (MRL/l) mice develop a lupus-like syndrome and a disease histologically and serologically similar to human rheumatoid arthritis. Their sera contain polyclonal IgM rheumatoid factors (RF) reactive with all murine IgG subclasses (frequently strongest with IgG2a) and several heterologous IgG. To examine the repertoire and epitopic specificities of these RF, we fused splenocytes from 3.5-mo-old seropositive MRL/l mice with appropriate myeloma partners and derived 1,723 hybridomas of which 23 secreted IgMRF. These monoclonal IgMRF bound to murine IgG only, not to other murine isotypes. Eight murine IgG subclass-specific clonotypes were identified. Most clones reacted with either multiple IgG subclasses or with IgG2a alone. A few clones reacted solely with IgG2b but none reacted exclusively with IgG1 or IgG3. Monoclonal IgMRF with exclusively anti-IgG2a activity exhibited allotypic specificity, reacting, with few exceptions, with a, c, and e, but not b, d, or j IgG2a allotypes. Four clonotypes could be distinguished by cross-reactivity with IgG from species other than mice. Monoclonals possessing activity against several murine subclasses cross-reacted extensively with heterologous IgG, including all human IgG subclasses without allotypic restrictions. Monoclonal IgMRF specific for murine IgG2a or 2b did not cross-react with heterologous IgG. Based on the absence of cross-reactions by IgG2a-specific monoclonal autoantibodies, certain peptides of the IgG CH2 and CH3 domains appear to generate the antigenic determinants of the anti-IgG2a RF in MRL/l mice. All of the monoclonal RF bound to Fc and, with one exception, not to Fab fragments of murine IgG. Binding of the monoclonal RF to substrate IgG was not inhibited by Clq, thus excluding the Clq-binding site at the CH2 domain as one of the responsible epitopes in the induction of MRL/l RF. mIgMRF could be categorized as strongly, weakly, or noninhibitable by protein A, which interacts with IgG molecules at or near the CH2-CH3 junction. Inhibition appears to be caused by conformational changes and/or steric shielding of certain IgG areas distant from this junction and not by identical binding sites between protein A and RF. Certain of the mIgMRF that were weakly or not at all inhibitable by protein A were found to cross-react equally well with human Fc (CH2-CH3 domains) and pFc' (CH3 domain) fragments, indicating that the binding site for these monoclonals is at the CH3 domain. Monoclonal RF were devoid of anti-double-strand DNA, anticollagen, or antipeptidoglycan pentapeptide cross-reactivity, but one of the monoclonals cross-reacted with histones, four with single-strand DNA, and one with both histones and single-strand DNA.