tbuckley/cabot-search huggingface dataset:
Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo.
Authors: M K Jenkins, R H Schwartz
Journal: The Journal of Experimental Medicine (1987)

We investigated the antigen specificity and presentation requirements for inactivation of T lymphocytes in vitro and in vivo. In vitro studies revealed that splenocytes treated with the crosslinker 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (ECDI) and soluble antigen fragments failed to stimulate significant proliferation by normal pigeon cytochrome c-specific T cell clones, suggesting that the chemical treatment inactivated full antigen presentation function. However, T cell clones exposed to ECDI-treated splenocytes and antigen in vitro were rendered unresponsive for at least 8 d to subsequent antigen stimulation with normal presenting cells. As predicted by the in vitro results, specific T cell unresponsiveness was also induced in vivo in B10.A mice injected intravenously with B10.A, but not B10.A(4R), splenocytes coupled with pigeon cytochrome c via ECDI. The antigen and MHC specificity of the induction of this T cell unresponsiveness in vitro and in vivo was identical to that required for T cell activation. These results suggest that nonmitogenic T cell recognition of antigen/MHC on ECDI-modified APCs results in the functional inactivation of T cell clones.
High death rate among heart transplant recipients prompts investigation
Authors: Adrian O'Dowd
Journal: BMJ (2007)

The prime minister set out his priorities for the health service in the Queen's speech this week-with plans to legislate for a new quality control regulator and changes in the way doctors are regulated and in the rules concerning assisted reproduction and embryo research.Gordon Brown used his first Queen's speech to announce the creation of a new regulator, whose aim will be "to ensure clean and safe services and high quality care."The new body for England, to be known as the Care Quality Commission (or Ofcare for short), will take over the functions of the Healthcare Commission, the Commission for Social Care Inspection, and the Mental Health Act Commission.It will be set up under the proposed Health and Social Care Bill and will have the authority to fine hospitals and shut down wards.The Health and Social Care Bill also includes UK-wide measures to abandon the criminal standard of proof (that is, beyond reasonable doubt) in cases where doctors' fitness to practise is questioned.Instead doctors could be struck off the medical register on the lower civil standard of "balance of probabilities."The draft Human Tissue and Embryo Bill, which was published in May this year, will also be debated in the next session of parliament.It aims to update the Human Fertilisation and Embryology Act 1990, which is based on scientific knowledge and debate from the 1980s.The new bill has already been criticised by a cross party group of MPs and peers, in a report published in August.The committee said that the new bill should include a provision to record on birth certificates the fact that a child has been born after egg or sperm donation.At the moment parents are not obliged to tell children that they were conceived from donated sperm or eggs, and children can't check who their biological parents are until they reach the age of 18. Queen speech gives plans for new health regulatorUK NEWS Annual incidence of MRSA falls in England, p 959 WoRld NEWS A �a��e�� of life o�� dea���� ��ina�s ���ansplan�a�ion p��ac�ice, p 9��A �a��e�� of life o�� dea���� ��ina�s ���ansplan�a�ion p��ac�ice, p 9�� , p 9�� b�j.co�Suicide ��a�e of �o�en doc�o��s in US is ��ice ��a� of o��e�� �o���ing �o�en Suicide ��a�e of �o�en doc�o��s in US is ��ice ��a� of o��e�� �o���ing �o�en
Oxidative Stress and Left Ventricular Function with Chronic Intermittent Hypoxia in Rats
Authors: Ling Chen, Elliot Einbinder, Qi Zhang, Jeffrey Hasday, C. William Balke, Steven M. Scharf
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Obstructive sleep apnea (OSA) is associated with oxidative stress and myocardial dysfunction. We hypothesized that the chronic intermittent hypoxia (CIH) component of OSA is sufficient to lead to these adverse effects.Rats were exposed to CIH (nadir O2, 4-5%) for 8 hours/day, 5 days/week, for 5 weeks. Results were compared with similarly handled controls (HC). Outcomes included blood pressure (tail cuff plethysmograph), echocardiographic and invasive measures of left-ventricular (LV) function, and indices of oxidative stress that included levels of myocardial lipid peroxides and Cu/Zn superoxide dismutase. Blood pressure was greater in CIH (n=22) than in HC (n=22) after 2 weeks of exposure (136+/-12 vs. 128+/-8 mm Hg; p<0.05). However, the difference disappeared by 5 weeks (127+/-13 vs. 127+/-13 mm Hg). LV weight/heart weight was greater with CIH (CIH, 0.52+/-0.05; HC, 0.47+/-0.06; p<0.005). Echocardiograms revealed LV dilation, as well as decreased LV fractional shortening (CIH, 29.7+/-9.8%; HC, 37.4+/-7.1%; p<0.001). LV end-diastolic pressure was increased with CIH (CIH, 13.7+/-5.5; HC, 8.0+/-2.9 mm Hg; p<0.001), decreased LV dp/dtmax (CIH, 5072+/-2191; HC, 6596+/-720 mm Hg/second; p<0.039), and decreased cardiac output (CIH, 48.2+/-10.5; HC, 64.1+/-10.9 ml/minute; p<0.001). LV myocardial lipid peroxides were greater (CIH, 1,258+/-703; HC 715+/-240 microm/mg protein; p<0.05) and LV myocardial superoxide dismutase levels were lower (CIH, 10.3+/-4.9; HC, 18.6+/-8.2 U/mg protein; p<0.05) with CIH.CIH leads to oxidative stress and LV myocardial dysfunction.
Casualty Out-Patients
Authors: H. N. Hardy
Journal: BMJ (1874)

<h3>Background</h3> Identifying patients with undifferentiated arthritis (UA) who are destined to develop rheumatoid arthritis (RA) is important to allow early institution of disease modifying therapy. <h3>Objectives</h3> To describe and compare the baseline characteristics of very early UA-patients developing RA according to the 2010 ACR/EULAR RA classification criteria (UA-RA) vs. not developing RA (UA-non-RA) over a 2-year follow-up period. <h3>Methods</h3> An early arthritis clinic was established as a prospective multi-center cohort study in 2004. Patients (18-75 years old) with ≥1 swollen joint of ≤16 weeks duration were included and followed for 2 years with examination at 0, 3, 6,12 and 24 months. A comprehensive data collection was undertaken, including a structured patient history, 66-swollen (SJC) and 28-tender joint counts (TJC), laboratory examinations and patients reported outcomes. Patients with osteoarthritis, septic arthritis or arthritis due to trauma were excluded. Mann-Whitney U-test, independent T-test and chi-square tests were used as appropriate to compare baseline characteristics between UA-non-RA and UA-RA patients. <h3>Results</h3> 1085 patients (pts) were included from 2004 to 2010 (mean(SD) age 46.1(14.9) years, 54.7% females, median (interquartile range (IQR)) duration of joint swelling 33(12,65) days). 658 pts (after excluding pts with other diagnoses) had available data for application of the 2010 ACR/EULAR RA classification criteria at baseline, and 236/658 (35.9%) fulfilled the criteria. Of the remaining 422 UA pts, only 27 further pts (6.4%) were classified as RA according to the criteria during follow-up. Distribution of criteria points at baseline in UA-RA pts:5 points n=11, 4 points n=7, 3 points n=6, 2 points, 1 point and 0 points n=1 each. In contrast, 20/395 (5.1%), of the UA-non-RA pts had 5 criteria points at baseline (p&lt;0.001). 13/20 (65.0%) of these pts were seronegative compared to 4/11 (36.4%) of the UA-RA pts (p=0.13). 21/27 (77.8%) of the UA-RA pts fulfilled the criteria within the first 6 months. Comparison of baseline characteristics between the two groups is shown in the table. <h3>Conclusions</h3> Only 6.4 % of patients with very early UA fulfilled the 2010 RA classification criteria during 2 years of follow-up, most of them fulfilled the criteria within the first 6 months. In univariate analyses female gender, smoking, seropositivity, higher joint counts and disability were associated with RA development. The number of patients with 5 criteria points at baseline was higher in the UA-RA vs. the UA-non-RA group. <h3>Disclosure of Interest</h3> None Declared
Decreased expression of an ATP-binding cassette transporter, MRP2, in human livers with hepatitis C virus infection
Authors: Eiji Hinoshita, Ken-ichi Taguchi, Akihiko Inokuchi, Takeshi Uchiumi, Naoko Kinukawa, Mitsuo Shimada, Masazumi Tsuneyoshi, Keizo Sugimachi, Michihiko Kuwano
Journal: Journal of Hepatology (2001)
Tmem64 Modulates Calcium Signaling during RANKL-Mediated Osteoclast Differentiation
Authors: Hyunsoo Kim, Taesoo Kim, Byung-Chul Jeong, Il-Taeg Cho, Daehee Han, Noriko Takegahara, Takako Negishi-Koga, Hiroshi Takayanagi, Jae Hee Lee, Jai-Yoon Sul, Vikram Prasad, Seoung Hoon Lee, Yongwon Choi
Journal: Cell Metabolism (2013)
The Rho protein exchange factor Vav3 regulates vascular smooth muscle cell proliferation and migration
Authors: Gilles Toumaniantz, David Ferland-McCollough, Chrystelle Cario-Toumaniantz, Pierre Pacaud, Gervaise Loirand
Journal: Cardiovascular Research (2009)

Rho guanine nucleotide exchange factors (Rho GEFs) are responsible for Rho protein activation by catalyzing the exchange of GDP for GTP. Although overactivation of Rho proteins is a common component of the pathogenesis of vascular disorders, the molecular mechanisms and the Rho GEFs regulating Rho protein activity and Rho-dependent functions in vascular smooth muscle cells (VSMC) are still unknown. The aim of this study was thus to identify Rho GEFs involved in the regulation of VSMC functions. By a functional screening based on small interfering RNA (siRNA)-mediated silencing of 27 Rho GEFs, we found that only silencing of the Rho GEF Vav3 inhibited rat VSMC proliferation. Conversely, overexpression of Vav3 potentiated VSMC proliferation, whereas the catalytically inactive Vav3 mutant had no effect. The stimulatory effect of Vav3 on VSMC proliferation was inhibited by the Src tyrosine kinase inhibitor SU6656 and by co-expression of the dominant-negative Rac1-N17 mutant. In agreement with this observation, expression of Vav3 induced enrichment of Rac1 to the membrane, activation of its effector PAK, and stimulated VSMC migration. Increased levels of Vav3 transcripts were found in stented arteries and arteries from hypertensive rats. Furthermore, siRNA targeting Vav3 decreased arterial wall cell proliferation. The Rho GEF Vav3 controls VSMC proliferation and migration through activation of Rac1/PAK signalling. Vav3 is a convergent point mediating Rac1 activation in response to different upstream mediators that promote VSMC proliferation and migration and thus appears to be a new potential therapeutic target that could be used to limit vascular proliferative diseases.
Microtubule-Disrupting Chemotherapeutics Result in Enhanced Proteasome-Mediated Degradation and Disappearance of Tubulin in Neural Cells
Authors: Lyn M. Huff, Dan L. Sackett, Marianne S. Poruchynsky, Tito Fojo
Journal: Cancer Research (2010)

We sought to examine the effects of microtubule-targeting agents (MTA) on neural cells to better understand the problem of neurotoxicity, their principal side effect, and to possibly develop a model of clinical toxicity. Studies showed that microtubule-depolymerizing agents (MDA) not only disassembled microtubules in neural HCN2 cells but also led to rapid disappearance of tubulin, and that this was specific for MDAs. Tubulin levels decreased to 20% as early as 8 hours after adding vincristine, and to 1% to 30% (mean, 9.8 +/- 7.6%; median of 7%) after 100 nmol/L vincristine for 24 hours. This disappearance was reversible. An increase in both glu-terminated and acetylated tubulin, markers of stable tubulin, preceded reaccumulation of soluble tubulin, suggesting a priority for stabilizing tubulin first as microtubules before replenishing the soluble pool. Similar results were shown with other MDAs. Furthermore, microtubule reassembly did not arise from a central focus but instead appeared to involve dispersed nucleation, as evidenced by the appearance of small, stable microtubule stubs throughout the cytoplasm. In contrast, experiments with four nonneural "normal" cell lines and four cancer cell lines resulted in microtubule destabilization but only modest tubulin degradation. Evidence for proteasome-mediated degradation was obtained by demonstrating that adding a proteasome inhibitor before vincristine prevented tubulin disappearance. In summary, MDAs lead to rapid disappearance of tubulin in neural but not in other normal or cancer cells. These results underscore the fine control that occurs in neural cells and may further our understanding of neurotoxicity following MDAs.
Anorexic Agents Aminorex, Fenfluramine, and Dexfenfluramine Inhibit Potassium Current in Rat Pulmonary Vascular Smooth Muscle and Cause Pulmonary Vasoconstriction
Authors: E. Kenneth Weir, Helen L. Reeve, James M.C. Huang, Evangelos Michelakis, Daniel P. Nelson, Vaclav Hampl, Stephen L. Archer
Journal: Circulation (1996)

Background The appetite suppressant aminorex fumarate is thought to have caused an epidemic of pulmonary hypertension in Europe in the 1960s. More recently, pulmonary hypertension has been described in some patients taking other amphetamine-like, anorexic agents: fenfluramine and its d -isomer, dexfenfluramine. No mechanism has been demonstrated that might account for the association between anorexic drugs and pulmonary hypertension. Methods and Results Using the whole-cell, patch-clamp technique, we found that aminorex, fenfluramine, and dexfenfluramine inhibit potassium current in smooth muscle cells taken from the small resistance pulmonary arteries of the rat lung. Dexfenfluramine causes reversible membrane depolarization in these cells. These actions are similar to those of hypoxia, which initiates pulmonary vasoconstriction by inhibiting a potassium current in pulmonary vascular smooth muscle. In the isolated, perfused rat lung, aminorex, fenfluramine, and dexfenfluramine induce a dose-related increase in perfusion pressure. When the production of endogenous NO is inhibited by N -nitro- l -arginine methyl ester, the pressor response to dexfenfluramine is greatly enhanced. Conclusions These observations indicate that anorexic agents, like hypoxia, can inhibit potassium current, cause membrane depolarization, and stimulate pulmonary vasoconstriction. They suggest one mechanism that could be responsible for initiating pulmonary hypertension in susceptible individuals. It is possible that susceptibility is the result of the reduced production of an endogenous vasodilator, such as NO, but this remains speculative.
Interlaboratory Evaluation of <i>in Vitro</i> Cytotoxicity and Inflammatory Responses to Engineered Nanomaterials: The NIEHS Nano GO Consortium
Authors: Tian Xia, Raymond F. Hamilton, James C. Bonner, Edward D. Crandall, Alison Elder, Farnoosh Fazlollahi, Teri A. Girtsman, Kwang Kim, Somenath Mitra, Susana A. Ntim, Galya Orr, Mani Tagmount, Alexia J. Taylor, Donatello Telesca, Ana Tolic, Christopher D. Vulpe, Andrea J. Walker, Xiang Wang, Frank A. Witzmann, Nianqiang Wu, Yumei Xie, Jeffery I. Zink, Andre Nel, Andrij Holian
Journal: Environmental Health Perspectives (2013)

Background: Differences in interlaboratory research protocols contribute to the conflicting data in the literature regarding engineered nanomaterial (ENM) bioactivity.Objectives: Grantees of a National Institute of Health Sciences (NIEHS)-funded consortium program performed two phases of in vitro testing with selected ENMs in an effort to identify and minimize sources of variability.Methods: Consortium program participants (CPPs) conducted ENM bioactivity evaluations on zinc oxide (ZnO), three forms of titanium dioxide (TiO2), and three forms of multiwalled carbon nanotubes (MWCNTs). In addition, CPPs performed bioassays using three mammalian cell lines (BEAS-2B, RLE-6TN, and THP-1) selected in order to cover two different species (rat and human), two different lung epithelial cells (alveolar type II and bronchial epithelial cells), and two different cell types (epithelial cells and macrophages). CPPs also measured cytotoxicity in all cell types while measuring inflammasome activation [interleukin-1β (IL-1β) release] using only THP-1 cells.Results: The overall in vitro toxicity profiles of ENM were as follows: ZnO was cytotoxic to all cell types at ≥ 50 μg/mL, but did not induce IL-1β. TiO2 was not cytotoxic except for the nanobelt form, which was cytotoxic and induced significant IL-1β production in THP-1 cells. MWCNTs did not produce cytotoxicity, but stimulated lower levels of IL-1β production in THP-1 cells, with the original MWCNT producing the most IL-1β.Conclusions: The results provide justification for the inclusion of mechanism-linked bioactivity assays along with traditional cytotoxicity assays for in vitro screening. In addition, the results suggest that conducting studies with multiple relevant cell types to avoid false-negative outcomes is critical for accurate evaluation of ENM bioactivity.
Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects
Authors: M. Maffei, J. Halaas, E. Ravussin, R.E. Pratley, G.H. Lee, Y. Zhang, H. Fei, S. Kim, R. Lallone, S. Ranganathan, P.A. Kern, J.M. Friedman
Journal: Nature Medicine (1995)
The Up-Regulation of Y-Box Binding Proteins (DNA Binding Protein A and Y-Box Binding Protein-1) as Prognostic Markers of Hepatocellular Carcinoma
Authors: Mahmut Yasen, Kazunori Kajino, Sayaka Kano, Hiroshi Tobita, Junji Yamamoto, Takeshi Uchiumi, Shigeyuki Kon, Masahiro Maeda, Gulanbar Obulhasim, Shigeki Arii, Okio Hino
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The development of hepatocellular carcinoma is associated with the chronic inflammation of the liver caused by various factors such as hepatitis B or C virus infection. Previously, we reported DNA binding protein A (dbpA) as a candidate molecule that can accelerate inflammation-induced hepatocarcinogenesis. DbpA belongs to the Y-box binding protein family, and Y-box binding protein-1 (YB-1), the prototype member of this family, is reported to be a prognostic marker of malignant diseases other than hepatocellular carcinoma. The purpose of this study is to examine the significance of the expression of dbpA or of the T-to-G transversion in the dbpA promoter region, which enhances the promoter activity in vitro, for the progression of hepatocellular carcinoma. Experimental Design: We studied the expression of dbpA (as well as of YB-1) in 82 formalin-fixed hepatocellular carcinoma tissues by immunohistochemistry and determined the sequence of the dbpA promoter region in 42 frozen hepatocellular carcinoma tissues. We examined the relationship between these findings and the clinicopathologic factors of hepatocellular carcinoma patients. Results: DbpA expression was associated with the advanced stages of hepatocellular carcinoma, and the cases with the nuclear dbpA expression had a poor prognosis. DbpA contributed more significantly to this association than YB-1. Furthermore, the T-to-G transversion in the dbpA promoter region was related to the nuclear localization of dbpA. Conclusion: DbpA was a more significant prognostic marker of hepatocellular carcinoma than YB-1. The T-to-G transversion in the dbpA promoter region was suggested to be a predisposing factor for the progression of hepatocellular carcinoma.
Lipid peroxidation, arachidonic acid and products of the lipoxygenase pathway in ischaemic preconditioning of rat heart
Authors: J Starkopf
Journal: Cardiovascular Research (1998)

Objective: Preconditioning with brief intermittent periods of ischaemia is known to provide protection against ischaemic injury. It has been suggested that myocardial ischaemia also activates phospholipase A2, which releases arachidonic acid from phospholipids. In the present study the possible role of phospholipid peroxidation, arachidonic acid and products of the lipoxygenase pathway in cellular mechanisms of ischaemic preconditioning was examined. Methods: Isolated, buffer-perfused rat hearts were freeze-clamped at the end of preconditioning (a cycle of 5 min global ischaemia +5 min reperfusion) and at the end of 30 min global ischaemia and analysed for non-esterified fatty acids and fatty acids in the 2-position of phospholipid. In a separate set of experiments, hearts pretreated with a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), were subjected to 30 min regional ischaemia and 120 min reperfusion. Infarct size was determined by tetrazolium staining and the ischaemic risk zone with fluorescent particles. Results: Myocardial levels of arachidonic as well as of linoleic and docosahexaenoic acid were significantly elevated by preconditioning. Also, the level of peroxidized polyunsaturated fatty acids (measured as hydroxy conjugated dienes) in myocardial phospholipid was significantly increased: 101.4±16.8 nmol/g versus 51.2±7.3 nmol/g tissue dw in the control group, p<0.05. Pre-treatment of hearts with 5 μM NDGA blocked the infarct limiting effect of preconditioning: infarct size was 37.4±6.4% of risk zone in control, 9.0±0.9% in the preconditioning group and 27.7±3.8% in the preconditioning+NDGA group (p<0.05 vs. IP, n.s. vs. control). Conclusion: Our findings provide evidence for the involvement of phospholipase A2 and lipoxygenase derived lipid second messengers in ischaemic preconditioning of the isolated rat heart.
Assessing Whether to Perform a Confirmatory Randomized Clinical Trial
Authors: M. K. B. Parmar, R. S. Ungerleider, R. Simon
Journal: JNCI Journal of the National Cancer Institute (1996)

A confirmatory randomized clinical trial is a trial that is aimed at assessing whether a treatment effect observed in a previous randomized trial (or trials) is real and important. There is often considerable disagreement about the need for such confirmatory trials. Our aim is to provide a general statistical framework for evaluating whether a confirmatory trial is warranted in a particular situation. The results of two clinical trials are considered: 1) a Cancer and Leukemia Group B trial comparing induction chemotherapy plus radiotherapy with radiotherapy alone in the treatment of patients with locally advanced non-small-cell lung cancer and 2) a North Central Cancer Treatment Group trial comparing surgery plus adjuvant chemotherapy with surgery alone in the treatment of patients with advanced colon cancer. In our analysis, we argue that differences in the interpretation of results from a randomized trial are based on differences in prior beliefs about the efficacy of the treatment(s) under study. We believe that a major factor in the decision to perform a confirmatory trial is prior skepticism about the clinical worth of the treatment in question. Both the level of prior skepticism and the minimum treatment effect deemed clinically worthwhile require subjective judgment We develop a Bayesian framework to allow differences in interpretation to be examined systematically and the need for a confirmatory trial to be assessed. Our model allows the addition of prior belief (specified in the form of a prior distribution of treatment effect) to the results of a trial to yield a posterior distribution. The interpretation of trial results is based on the posterior distribution and will vary as the prior distribution (i.e., the prior belief) varies. To aid in the interpretation of trial results, we also advocate the specification of a minimum clinically worthwhile treatment effect at the start of a trial. Our approach acknowledges that a number of different prior beliefs are possible, giving rise to a range of interpretations of results from a clinical trial. This approach provides a formal and systematic basis for considering both the range of likely opinions and the subsequent decision to be made with regard to the need for a confirmatory trial. We recommend that this approach be considered in the discussion of future confirmatory randomized clinical trials.