tbuckley/cabot-search huggingface dataset:
Effective Treatment of Metastatic Forms of Epstein-Barr Virus–Associated Nasopharyngeal Carcinoma with a Novel Adenovirus-Based Adoptive Immunotherapy
Authors: Corey Smith, Janice Tsang, Leone Beagley, Daniel Chua, Victor Lee, Vivian Li, Denis J. Moss, William Coman, Kwok H. Chan, John Nicholls, Dora Kwong, Rajiv Khanna
Journal: Cancer Research (2012)

Nasopharyngeal carcinoma (NPC) is endemic in China and Southeast Asia where it is tightly associated with infections by Epstein-Barr virus (EBV). The role of tumor-associated viral antigens in NPC renders it an appealing candidate for cellular immunotherapy. In earlier preclinical studies, a novel adenoviral vector-based vaccine termed AdE1-LMPpoly has been generated that encodes EBV nuclear antigen-1 (EBNA1) fused to multiple CD8(+) T-cell epitopes from the EBV latent membrane proteins, LMP1 and LMP2. Here, we report the findings of a formal clinical assessment of AdE1-LMPpoly as an immunotherapeutic tool for EBV-associated recurrent and metastatic NPC. From a total of 24 patients with NPC, EBV-specific T cells were successfully expanded from 16 patients with NPC (72.7%), whereas six patients with NPC (27.3%) showed minimal or no expansion of virus-specific T cells. Transient increase in the frequencies of LMP1&2- and EBNA1-specific T-cell responses was observed after adoptive transfer to be associated with grade I flu-like symptoms and malaise. The time to progression in these patients ranged from 38 to 420 days with a mean time to progression of 136 days. Compared with patients who did not receive T cells, the median overall survival increased from 220 to 523 days. Taken together, our findings show that adoptive immunotherapy with AdE1-LMPpoly vaccine is safe and well tolerated and may offer clinical benefit to patients with NPC.
Extra money targeted at emergency services may not have been used for frontline care, say experts
Authors: A. O'Dowd
Journal: BMJ (2015)

Experts have warned that extra money intended to help with this winter’s pressures on accident and emergency departments in hospitals in England may not have been spent on frontline care and could have gone instead to help trusts tackle their deficits.

MPs on the parliamentary health select committee were told that information was now being sought by doctors’ representatives to ascertain exactly how money has been spent on winter pressures. The committee held an urgent evidence session on 14 January for a new inquiry into accident and emergency services. It follows recent concerns over current pressures on emergency departments, given that performance on targets for these services has dropped to its lowest in 10 years.1

MPs asked what had …
Microbiological quality and quality control of purified water and ultrapure dialysis fluids for online hemodiafiltration in routine clinical practice
Authors: E. Lars Penne, Linda Visser, Marinus A. van den Dorpel, Neelke C. van der Weerd, Albert H.A. Mazairac, Brigit C. van Jaarsveld, Marion G. Koopman, Pieter Vos, Geert W. Feith, Ton K. Kremer Hovinga, Henk W. van Hamersvelt, Inge M. Wauters, Michiel L. Bots, Menso J. Nubé, Piet M. ter Wee, Peter J. Blankestijn, Muriel P.C. Grooteman
Journal: Kidney International (2009)
Does long-term metformin treatment increase cardiac lipoprotein lipase?
Authors: David Hauton
Journal: Metabolism (2010)

Acute activation of adenosine monophosphate-activated protein kinase (AMPK) or jumps in cardiac work increased cardiac endothelial lipoprotein lipase (LPL), yet it is unclear whether chronic AMPK activation maintains this elevated LPL. To activate AMPK chronically, metformin at low (300 mg/kg/d) and high dose (600 mg/kg/d) was administered in drinking water for 14 days. Control, metformin-treated, and 5-amino-imidazole-4-carboxamide riboside (AICAR)-treated (0.5 mmol/L) ex vivo hearts were perfused to investigate uptake of triacylglycerol and cardiac LPL activity. For perfused rat hearts, increased uptake of labeled Intralipid and β-oxidation of Intralipid-fatty acid were noted for both AICAR (P < .05) and high-dose metformin (P < .01). Intralipid incorporation into tissue lipids was decreased by AICAR (P < .05) and increased after high-dose metformin (P < .05), the increase manifest as enhanced triacylglycerol deposition (P < .05). Low-dose metformin did not alter lipid uptake or tissue deposition. Both high-dose metformin and AICAR decreased cardiac acetyl-coenzyme A carboxylase activity (P < .01). Heparin-releasable LPL was increased after treatment with AICAR (P < .05) and high-dose metformin (P < .01). Low-dose metformin did not alter cardiac LPL. High-dose metformin doubled immunoreactive AMPK and phospho-AMPK protein (P < .001) and increased phosphorylation of p38-mitogen-activated protein kinase (P < .05). After heparin pretreatment, the rate of recruitment of LPL to the cardiac endothelium was increased by AICAR (P < .05) but not by high-dose metformin. These data suggest that AMPK activation increased cardiac endothelial LPL, yet acute and chronic activation of AMPK may yield increased LPL through differing mechanisms.
The form of chaos in the noisy brain can manifest function
Authors: Ichiro Tsuda
Journal: Behavioral and Brain Sciences (1996)

Abstract I would like to emphasize the significance of chaotic dynamics at both local and macroscopic levels in the cortex. The basic notions dealt with in this commentary will be noise-induced order, chaotic “itinerancy” and dissipative structure. Wright &amp; Laley's theory would be partially misleading, since emergent nonlinearity rather than the linearity at even a macroscopic level can actually subserve cortical functions.
Age associated changes in membrane currents in rat ventricular myocytes
Authors: K E Walker, E G Lakatta, S R Houser
Journal: Cardiovascular Research (1993)

Objective: Action potential duration of senescent rat ventricular myocytes is longer than in young adults. The aim of the study was to determine whether age related changes in L-type calcium current (Ica), transient outward potassium current (ITo). and inwardly rectifying potassium current (IK1) are involved in the prolongation of the early (ICa, ITo) and late (IK1) portions of the rat action potential plateau. Methods: Whole cell voltage clamp techniques were used to study these currents in ventricular myocytes isolated from young (2-3 months), middle aged (8-9 months), and senescent (21-25 months) rats. Results: There were no differences in the magnitude of ICa among age groups once currents were normalised for capacitative surface area. The voltage dependence of ICa activation and steady state inactivation in the three age groups was also similar. At test potentials of 0 and +10 mV, there was a significant (p ≤ 0.05) slowing in the time course of inactivation of Ica; the time constants of inactivation increased with age [young v old in ms(SEM): 0 mV, 22.2(2.2) v 38.0(5.0) (slow); +10 mV, 80(2.0) v 15.6(2.0) (fast)]. With internal EGTA to buffer intracellular Ca2+, no significant age related differences in action potential duration or the time course of ICa inactivation were observed. There was an age associated decrease in peak ITO density in the old (n=25) compared to the young (n=25) cell group (p < 0.05). The only age associated change in the kinetic properties of ITO was a small but consistent slowing in the time constants of inactivation at most test voltages measured. with significance occurring at 0 mV in the slow (τ2) component. Conclusions: ICa density is maintained in senescence; Ica inactivation, however, is slowed. Age related differences in action potential duration and ICa inactivation were reduced by buffering intracellular Ca2+. ITo channels appear to retain normal function through the aging process but overall there is a reduced channel density. The age associated changes in these currents should contribute to prolongation of action potential duration of the early plateau phase seen in the senescent rat. Cardiovascular Research 1993;27:1968-1977
Meta-analysis identifies six new susceptibility loci for atrial fibrillation
Authors: Patrick T Ellinor, Kathryn L Lunetta, Christine M Albert, Nicole L Glazer, Marylyn D Ritchie, Albert V Smith, Dan E Arking, Martina Müller-Nurasyid, Bouwe P Krijthe, Steven A Lubitz, Joshua C Bis, Mina K Chung, Marcus Dörr, Kouichi Ozaki, Jason D Roberts, J Gustav Smith, Arne Pfeufer, Moritz F Sinner, Kurt Lohman, Jingzhong Ding, Nicholas L Smith, Jonathan D Smith, Michiel Rienstra, Kenneth M Rice, David R Van Wagoner, Jared W Magnani, Reza Wakili, Sebastian Clauss, Jerome I Rotter, Gerhard Steinbeck, Lenore J Launer, Robert W Davies, Matthew Borkovich, Tamara B Harris, Honghuang Lin, Uwe Völker, Henry Völzke, David J Milan, Albert Hofman, Eric Boerwinkle, Lin Y Chen, Elsayed Z Soliman, Benjamin F Voight, Guo Li, Aravinda Chakravarti, Michiaki Kubo, Usha B Tedrow, Lynda M Rose, Paul M Ridker, David Conen, Tatsuhiko Tsunoda, Tetsushi Furukawa, Nona Sotoodehnia, Siyan Xu, Naoyuki Kamatani, Daniel Levy, Yusuke Nakamura, Babar Parvez, Saagar Mahida, Karen L Furie, Jonathan Rosand, Raafia Muhammad, Bruce M Psaty, Thomas Meitinger, Siegfried Perz, H-Erich Wichmann, Jacqueline C M Witteman, W H Linda Kao, Sekar Kathiresan, Dan M Roden, Andre G Uitterlinden, Fernando Rivadeneira, Barbara McKnight, Marketa Sjögren, Anne B Newman, Yongmei Liu, Michael H Gollob, Olle Melander, Toshihiro Tanaka, Bruno H Ch Stricker, Stephan B Felix, Alvaro Alonso, Dawood Darbar, John Barnard, Daniel I Chasman, Susan R Heckbert, Emelia J Benjamin, Vilmundur Gudnason, Stefan Kääb
Journal: Nature Genetics (2012)
P164 ntprobnp Predicts Survival And More Accurately Reflects Changing Right Ventricular Structure And Function Than 6mwd In Pulmonary Hypertension
Authors: M. Brewis, M. Johnson, A. Peacock
Journal: Thorax (2014)

<h3></h3> Right ventricular (RV) function is known to predict survival in pulmonary hypertension (PH). Furthermore, increasing right ventricular volumes (RVEDVI, RV end diastolic volume and RVESVI, RV end systolic volume index) and falling ejection fraction (RVEF) whilst on treatment have been shown to determine poorer outcome.<sup>1</sup> Measurement of RV function by cardiac MRI (CMR) is not widely available and often poorly tolerated in very breathless patients. Monitoring of PH patients traditionally focuses on serial 6 min walk testing (6MWD) and N terminal pro brain natriuretic peptide (NTproBNP), a biomarker that has been shown to reflect RV function and structure.<sup>2</sup> We hypothesised that ∆NTproBNP is a superior non invasive marker of ∆RV function than ∆6MWD, and predicts survival. <h3>Methods</h3> 59 patients with precapillary PH whom underwent serial CMR between 2004 and 2014 with 6MWD and/or NTproBNP sampling within 1 month of scan were retrospectively included. 146 ∆RV function values were calculated. For survival analysis, patients were censored at last day of study (24/6/14) or if lost to follow up. Survival was taken from the date of the second CMR scan. Due to the interaction between cardiac MRI values, only univariate survival analysis was performed. <h3>Results</h3> ∆NTproBNP correlates more closely with ∆RVEF, ∆RVEDVI, ∆RVESVI than 6MWD (table1). Both ∆NTproBNP and ∆6MWD predicted survival [HR 1.001 95% CI 1.001–1.002 p <h3>Conclusion</h3> ∆NTproBNP is superior to ∆6MWD as a surrogate marker of changing RV function which can be easily evaluated in the clinic setting. Both ∆NTproBNP and ∆ 6MWD predict survival in PH. <h3>References</h3> van Wolferen SA, Marcus JT, Boonstra A, Marques KMJ, Bronzwaer JGF, Spreeuwenberg MD, <i>et al</i>. Prognostic value of right ventricular mass, volume, and function in idiopathic pulmonary arterial hypertension. <i>European Heart Journal</i>. 2007;28(10):1250–7 Blyth KG, Groenning BA, Mark PB, Martin TN, Foster JE, Steedman T, <i>et al</i>. NT-proBNP can be used to detect right ventricular systolic dysfunction in pulmonary hypertension. <i>European Respiratory Journal</i>. 2007;29(4):737–44
Variability of clinical and laboratory features among patients with ribonuclease mitochondrial RNA processing endoribonuclease gene mutations
Authors: Fotini D. Kavadas, Silvia Giliani, Yiping Gu, Evelina Mazzolari, Andrea Bates, Eleonora Pegoiani, Chaim M. Roifman, Luigi D. Notarangelo
Journal: Journal of Allergy and Clinical Immunology (2008)
Hormones in Cosmetics
Authors: John S. Strauss
Journal: JAMA (1963)

In review of experimental data on the use of sex steroids in cosmetics, there was evidence that some topically applied steroidal hormones, both active and inactive biologically, cause slighthistologicalthickening of the epidermis of aged skin. Dermal changes are questionable and clinical effects usually negligible. In the amounts which can be safely incorporated into cosmetic preparations, topically applied estrogens have no effect on human sebaceous glands and oil secretion. Natural progesterone inphysiological amountscauses no increase in oil secretion in the human. Used as directed, topically applied hormones as presently formulated in cosmetic preparations have adequate safety factors.
Detection of Antibodies Against the Polymerase Gene Product in Hepatitis B Virus Infection
Authors: Nobukazu Yuki, Norio Hayashi, Akinori Kasahara, Kazuhiro Katayama, Keiji Ueda, Hideyuki Fusamoto, Takenobu Kamada
Journal: Hepatology (1990)

We have studied antibodies (anti-pol antibody) against the polymerase gene product of hepatitis B virus by solid-phase enzyme immunoassay using synthetic peptides coded for by this gene. Sera from six patients with acute hepatitis B, 112 chronic hepatitis B virus carriers and six healthy individuals with naturally acquired immunity to hepatitis B virus were tested for anti-pol antibody. In acute hepatitis B virus infection, anti-pol antibody was detected in three of six patients. In chronic hepatitis B virus infection, anti-pol antibody was detected in 17 of 29 (59%), in 23 of 33 (70%) of cirrhotic patients and in 18 of 24 (75%) patients with cirrhosis complicated by hepatocellular carcinoma, compared with 4 of 19 (21%) asymptomatic carriers and 2 of 7 (29%) patients with chronic persistent hepatitis. Titers of anti-pol antibody were higher in cirrhotic patients with and without hepatocellular carcinoma than in patients with chronic active hepatitis. The presence of anti-pol antibody, however, had no relationship with hepatitis B virus-associated DNA polymerase activities and other viral replicative markers. As for sera from six healthy individuals with naturally acquired immunity to hepatitis B virus, two (33%) were positive for anti-pol antibody. These results indicate that the immune response toward the polymerase gene product is induced during acute and chronic hepatitis B virus infection. In chronic hepatitis B virus infection, anti-pol antibody may serve as a new marker indicative of a long period of hepatitis B virus-induced hepatitis.
High Nuclear Poly(Adenosine Diphosphate-Ribose) Polymerase Expression Is Predictive for <i>BRCA1</i>- and <i>BRCA2</i>-Deficient Breast Cancer
Authors: Luka Ozretić, Kerstin Rhiem, Sebastian Huss, Barbara Wappenschmidt, Birgid Markiefka, Peter Sinn, Rita K. Schmutzler, Reinhard Buettner
Journal: Journal of Clinical Oncology (2011)
Evidence That Outwardly Rectifying Cl <sup>−</sup> Channels Underlie Volume-Regulated Cl <sup>−</sup> Currents in Heart
Authors: Dayue Duan, Joseph R. Hume, Stanley Nattel
Journal: Circulation Research (1997)

Swelling-induced Cl − current (I Cl.swell ) is present in most cardiac tissues, but the unitary channel underlying I Cl.swell is unknown. We used the cell-attached patch-clamp technique to assess the properties of single channels underlying I Cl.swell and the basally active Cl − current (I Cl.b ) in rabbit atrial myocytes. Under isotonic conditions, single outwardly rectifying Cl − channels (ORCCs) with a slope conductance of 28±1 pS at the reversal potential were observed in 21 (5.7%) of 367 patches. Unconditional kinetic analysis revealed at least three open and four closed-channel states. Hypotonic superfusion-induced swelling resulted in the appearance of active channels in 41 (15.5%) of 265 patches without channel activity under isotonic conditions and caused a second active channel to appear in 3 of 14 patches showing a single channel under isotonic conditions. Overall, channels were seen in 54 of 336 patches under hypotonic conditions (16.1%, P &lt;.001 versus isotonic conditions). The current-voltage relations, reversal potential–[Cl − ] o relations, open probability, and kinetics of swelling-induced channels were indistinguishable from those of ORCCs under isotonic conditions. Unitary ORCCs, I Cl.b , and I Cl.swell were strongly and similarly inhibited by tamoxifen. Swelling-induced increases in macroscopic Cl − current were attributable to an increase in the number of active ORCCs with no significant effects on single-channel amplitude or open probability. Estimated macroscopic currents based on cell surface area, patch dimensions, single-channel ORCC current amplitude, open probability, and density were consistent with measured values of I Cl.b and I Cl.swell . We conclude that ORCCs underlie volume-regulated basal and swelling-induced Cl − currents in isolated rabbit atrial myocytes.
CD4+ follicular helper T cell infiltration predicts breast cancer survival
Authors: Chunyan Gu-Trantien, Sherene Loi, Soizic Garaud, Carole Equeter, Myriam Libin, Alexandre de Wind, Marie Ravoet, Hélène Le Buanec, Catherine Sibille, Germain Manfouo-Foutsop, Isabelle Veys, Benjamin Haibe-Kains, Sandeep K. Singhal, Stefan Michiels, Françoise Rothé, Roberto Salgado, Hugues Duvillier, Michail Ignatiadis, Christine Desmedt, Dominique Bron, Denis Larsimont, Martine Piccart, Christos Sotiriou, Karen Willard-Gallo
Journal: Journal of Clinical Investigation (2013)

CD4⁺ T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce an image of CD4⁺ T cells infiltrating breast tumors using limited ex vivo manipulation to better understand the in vivo differences associated with patient prognosis. We performed comprehensive molecular profiling of infiltrating CD4⁺ T cells isolated from untreated invasive primary tumors and found that the infiltrating T cell subpopulations included follicular helper T (Tfh) cells, which have not previously been found in solid tumors, as well as Th1, Th2, and Th17 effector memory cells and Tregs. T cell signaling pathway alterations included a mixture of activation and suppression characterized by restricted cytokine/chemokine production, which inversely paralleled lymphoid infiltration levels and could be reproduced in activated donor CD4⁺ T cells treated with primary tumor supernatant. A comparison of extensively versus minimally infiltrated tumors showed that CXCL13-producing CD4⁺ Tfh cells distinguish extensive immune infiltrates, principally located in tertiary lymphoid structure germinal centers. An 8-gene Tfh signature, signifying organized antitumor immunity, robustly predicted survival or preoperative response to chemotherapy. Our identification of CD4⁺ Tfh cells in breast cancer suggests that they are an important immune element whose presence in the tumor is a prognostic factor.
Is waking electroencephalographic activity a predictor of daytime sleepiness in sleep-related breathing disorders?
Authors: E. Sforza, S. Grandin, C. Jouny, T. Rochat, V. Ibanez
Journal: European Respiratory Journal (2002)

No data are available in the literature assessing the potential use of waking electroencephalographic (EEG) activity in the detection of excessive daytime sleepiness (EDS) in patients with sleep-related breathing disorders (SRBD). The aim of this study was to evaluate whether waking EEG spectral power reflects the level of EDS in SRBD patients. The study was performed in 48 patients in whom quantitative EEG analysis, including the alpha attenuation coefficient (AAC), was performed. Sleepiness was assessed by the Epworth Sleepiness Scale, the Stanford Sleepiness Scale, the Visual Analogue Scale and the maintenance of wakefulness test. Although AAC and EEG spectral power tended to vary throughout the day, none of these variations correlated with EDS measures. Waking EEG measures were not different between snorers and apnoeic patients. Compared to nonsleepy patients, sleepy patients had greater theta and slow alpha powers, but the differences did not reach statistical significance. The EEG slowing was independent of hypoxaemia, severity of SRBD, or degree of sleep disruption. The authors conclude that waking electroencephalographic measures are not sensitive enough to predict variation in alertness or to differentiate sleepy from nonsleepy sleep-related breathing disorders patients. The degree of electroencephalographic slowing was related neither to sleep disruption nor to severity of sleep-related breathing disorders.
Virus-triggered immune suppression in mice caused by virus-specific cytotoxic T cells.
Authors: T P Leist, E Rüedi, R M Zinkernagel
Journal: The Journal of Experimental Medicine (1988)

Normal mice infected with 10(5) infectious doses of lymphocytic choriomeningitis virus (LCMV, WE isolate) generated a reduced or no T cell-independent IgM and/or T cell-dependent IgG response to a subsequent vesicular stomatitis virus Indiana (VSV-IND) injection; this transient immune suppression lasted for weeks to months. Connatally infected LCMV-carrier mice or acutely infected T cell-deficient nude mice had normal anti-VSV IgM and IgG or IgM responses respectively. LCMV-infected nude mice transfused with helper cell-depleted LCMV-specific immune spleen cells were immunosuppressed. Normal mice infected with LCMV but treated with a rat anti-CD8 mAb (that had been shown previously to eliminate cytotoxic T cells in vivo) and then infected with VSV exhibited a normal anti-VSV IgM and IgG response. Since no IFN-alpha or -beta was detected on, or after, day 6 of LCMV infection, neither LCMV alone, nor IFN induced by it caused the observed immune suppression; the presented evidence suggests that LCMV-immune CD8+ T cells were responsible for it. It is conceivable that a similar pathogenesis where virus-specific cytotoxic T cells may destroy virus-infected cells essentially involved in an immune response (APC, T helper cells, etc.) may be involved in other virally triggered immune suppression or in AIDS.
Clinical research in trust hospitals: Threatened by liability for negligence
Authors: D W Vere
Journal: BMJ (1993)

In deprived areas general practitioners need to work in the community with community health workers, benefits rights workers, health promotion officers, and housing officers to ameliorate the multifactorial problems caused by socioeconomic, educational, and health deprivation.Social policies aimed at a more equitable distribution of wealthby empowering deprived people through educa- tional and employment opportunities-are needed to reverse the dramatic widening of the healthwealth gap.5The message is clear.To reverse the marginalisation of disadvantaged areas additional resources must be targeted in health, education, and employment if the targets of The Health of the Nation are to have any chance of being met.Disproportionately greater resources are needed to give deprived people an average chance of health.