tbuckley/cabot-search huggingface dataset:
Constraints on Consultants
Authors: I. Atkin
Journal: BMJ (1973)

were demonstrated in normal subjects.'Sir Thomas Lewis showed in 19272 that intra- cutaneous morphine elicited a triple re- sponse similar to that induced by histamine.Histamine release by opium alkaloids has been demonstrated in isolated cat skin and muscle preparations.3Elevated plasma levels of histamine have been measured in intact dogs following the administration of morphine and pethidine.4A significant de- crease in the lung capacity of intact dogs has been observed following the administra- tion of morphine and pethidine-an effect most likely to be due to bronchoconstriction.5 The mechanism of opiate-induced bronchoconstriction may include central vagal stimulation, histamine release leading to enhanced bronchomotor tone and pul- monary vascular congestion, and histamine- induced reflex enhancement of vagal tone.5In view of this evidence and the availability of alternative sedatives, we feel that the use of opium alkaloids in asthma is unjustified and should be avoided.-Weare, etc.
Induction of Immune Tolerance to FIX Following Muscular AAV Gene Transfer Is AAV-dose/FIX-level Dependent
Authors: Meagan E Kelly, Jiacai Zhuo, Arpita S Bharadwaj, Hengjun Chao
Journal: Molecular Therapy (2009)

Direct intramuscular injection (IM) of adeno-associated virus (AAV) has been proven a safe and potentially efficient procedure for gene therapy of many genetic diseases including hemophilia B. It is, however, contentious whether high antigen level induces tolerance or immunity to coagulation factor IX (FIX) following IM of AAV. We recently reported induction of FIX-specific immune tolerance by IM of AAV serotype one (AAV1) vector in mice. We hypothesize that the expression of high levels of FIX is critical to induction of FIX tolerance. In this study, we investigated the correlation among AAV dose, FIX expression, and tolerance induction. We observed that induction of immune tolerance or immunity to FIX was dependent on the dose of AAV1-human FIX (hFIX) given and the level of FIX antigen expressed in both normal and hemophilia mice. We then defined the minimum AAV1-hFIX dose and the lowest level of FIX needed for FIX tolerance. Different from hepatic AAV-hFIX gene transfer, we found that FIX tolerance induced by IM of AAV1 was not driven by regulatory T cells. These results provided further insight into the mechanism(s) of FIX tolerance, contributing to development of hemophilia gene therapy, and optimization of FIX tolerance induction protocols.
Contractile properties and Ca2+ release activity of the sarcoplasmic reticulum in dilated cardiomyopathy.
Authors: A D'Agnolo, G B Luciani, A Mazzucco, V Gallucci, G Salviati
Journal: Circulation (1992)

BACKGROUND We performed a comparative study on Ca2+ release activity of the sarcoplasmic reticulum and calcium sensitivity of contractile apparatus of chemically skinned myocardial fibers obtained from four nonfailing human hearts and 13 excised hearts from patients with idiopathic dilated cardiomyopathy. METHODS AND RESULTS Ca2+ sensitivity of contractile apparatus was studied by following the isometric tension developed by chemically skinned myocardial fibers challenged with solutions of decreasing pCa. Ca2+ release from sarcoplasmic reticulum was monitored indirectly by measurement of the isometric tension developed by skinned fibers challenged with caffeine. We observed no significant difference of Ca2+ sensitivity and cooperativity between normal myocardium (pCa50 = 6.00 +/- 0.05; Hill coefficient, nHill = 2.07 +/- 0.10) and dilated cardiomyopathy (pCa50 = 6.03 +/- 0.07; nHill = 2.72 +/- 0.30) when the fibers were stretched to 130% of the resting length. We also found that both in normal myocardium and dilated cardiomyopathy, stretching to 150% of the resting length increased the Ca2+ sensitivity of the contractile system; pCa50 = 6.21 +/- 0.01 and 6.13 +/- 0.04 in normal and dilated cardiomyopathy, respectively, whereas in dilated cardiomyopathy there was a decrease of Hill coefficient with stretching that was not observed in the control group. The caffeine threshold in idiopathic dilated cardiomyopathy was markedly increased compared with the control group, 1.94 +/- 0.27 mmol/l and 0.29 +/- 0.04 mmol/l caffeine, respectively, whereas there were no significant differences in the extent and rate of caffeine-induced Ca2+ release. CONCLUSIONS These results indicate that in idiopathic dilated cardiomyopathy there is no alteration of contractile and regulatory proteins; on the contrary, the gating mechanism of the Ca2+ release channel of sarcoplasmic reticulum is abnormal, suggesting a possible involvement of the excitation-contraction coupling in the pathogenesis of this disease. It should also be taken into account, however, that the increased caffeine threshold in dilated cardiomyopathy would be a result of the enhanced resistance to the skinning procedure secondary to the modification of lipid species and/or content in sarcoplasmic reticulum membrane.
Netrin-1 controls sympathetic arterial innervation
Authors: Isabelle Brunet, Emma Gordon, Jinah Han, Brunella Cristofaro, Dong Broqueres-You, Chun Liu, Karine Bouvrée, Jiasheng Zhang, Raquel del Toro, Thomas Mathivet, Bruno Larrivée, Julia Jagu, Laurence Pibouin-Fragner, Luc Pardanaud, Maria J.C. Machado, Timothy E. Kennedy, Zhen Zhuang, Michael Simons, Bernard I. Levy, Marc Tessier-Lavigne, Almut Grenz, Holger Eltzschig, Anne Eichmann
Journal: Journal of Clinical Investigation (2014)

Autonomic sympathetic nerves innervate peripheral resistance arteries, thereby regulating vascular tone and controlling blood supply to organs. Despite the fundamental importance of blood flow control, how sympathetic arterial innervation develops remains largely unknown. Here, we identified the axon guidance cue netrin-1 as an essential factor required for development of arterial innervation in mice. Netrin-1 was produced by arterial smooth muscle cells (SMCs) at the onset of innervation, and arterial innervation required the interaction of netrin-1 with its receptor, deleted in colorectal cancer (DCC), on sympathetic growth cones. Function-blocking approaches, including cell type–specific deletion of the genes encoding Ntn1 in SMCs and Dcc in sympathetic neurons, led to severe and selective reduction of sympathetic innervation and to defective vasoconstriction in resistance arteries. These findings indicate that netrin-1 and DCC are critical for the control of arterial innervation and blood flow regulation in peripheral organs.
One Man's Burden
Authors: M. O'Donnell
Journal: BMJ (1984)

A former general practitioner discusses the dilemma of whether or not physicians always should tell patients the truth about their illnesses, particularly when the prognosis is not good. O'Donnell cautions against adopting an absolute rule of always disclosing everything, and acknowledges the difficulties of coping with patient ambivalence on the issue. He cites a 1981 study by Dr. John Spencer Jones wherein patients being treated for inoperable cancer were given the option of being told their diagnosis only if they asked. Half asked; half did not. O'Donnell concludes that, while some patients prefer uncertainty, others welcome the truth and the chance to reassess their lives before dying.
Choice of Psychotrophic Drugs
Authors: Ronald Pies
Journal: JAMA (1984)

<h3>To the Editor.—</h3> The study by Mellinger et al<sup>1</sup>is a valuable contribution to our knowledge of anxiolytic use. It raises two issues, however, that should lead physicians to question their manner of prescribing benzodiazepine anxiolytics. The study notes that many long-term users of anxiolytics show high levels of both anxiety and<i>depression</i>. The study further notes that many long-term users suffer from such painful conditions as arthritis, bursitis, and tenosynovitis. Physicians should view these findings with concern. The standard anxiolytics—alprazolam (Xanax) seems exceptional in this regard—may worsen depression or even suicidal ideation.<sup>2</sup>Anxious, depressed patients are better treated with a sedating antidepressant, such as trazodone hydrochloride (Desyrel).<sup>3</sup> Moreover, because benzodiazepines inhibit serotonin release, there is reason to believe they may<i>increase</i>pain perception. In contrast, antidepressants may be useful analgesics.<sup>4</sup>In short, antidepressants may be useful in treating the anxious, depressed, pain-ridden patient.
Mechanism of Adenosine-Induced Elevation of Pulmonary Capillary Wedge Pressure in Humans
Authors: Amit Nussbacher, Sigemituzo Ariê, Roberto Kalil, Pedro Horta, Marc D. Feldman, Giovanni Bellotti, Fulvio Pileggi, Mark Ellis, William H. Johnson, Gustavo B. Camarano, David A. Kass
Journal: Circulation (1995)

Background Continuous intravenous administration of adenosine to humans often results in a paradoxical rise in pulmonary capillary wedge pressure (PCWP), whereas arterial resistance is lowered and cardiac output and heart rate increase. This is believed to be due to diastolic stiffening of the ventricle or to a negative inotropic effect. In the present study, we tested these and other mechanisms by using pressure–volume (PV) analysis and echocardiography. Methods and Results Fifteen patients with normal rest left ventricular function underwent cardiac catheterization and received adenosine at a rate of 140 μg/kg per minute IV for 6 to 10 minutes. PV relations were measured in 9 patients (without coronary artery disease) using the conductance catheter method. In 6 additional patients with coronary artery disease, echocardiograms were used to assess wall thickness and function, and aortic and coronary sinus blood, lactate, oxygen, and adenosine levels were measured. Adenosine increased PCWP by 19% (+2.6 mm Hg) in both patient groups while lowering arterial load by 30% and increasing cardiac output by 45% (all P &lt;.001). There was no significant effect of adenosine on mean linear chamber compliance or monoexponential elastic stiffness, as the diastolic PV relation was unchanged in most patients. Diastolic wall thickness also was unaltered. Thus, the PCWP rise did not appear to be due to diastolic stiffening. Adenosine induced a rightward shift of the end-systolic PV relation (ESPVR) (+12.7±3.7 mL) without a slope change. This shift likely reflected effects of afterload reduction, as other indexes (stroke work–end-diastolic volume relation and dP/dt max at matched preload) were either unchanged or increased. Furthermore, this modest shift in ESPVR was more than compensated for by vasodilation and tachycardia, so reduced systolic function could not explain the increase in PCWP. There also was no net lactate production to suggest ischemia. Rather than arising from direct myocardial effects, PCWP elevation was most easily explained by a change in vascular loading, as both left ventricular end-diastolic volume and right atrial pressure increased ( P &lt;.05). This suggests that adenosine induced a redistribution of blood volume toward the central thorax. Conclusions PCWP elevation in response to adenosine primarily results from changes in vascular loading rather than from direct effects on cardiac diastolic or systolic function.
Abstract 2616: Thioredoxin reductase 1 modulates methylseleninic acid-induced redox status effects in A549 human lung cancer cells
Authors: Robyn L. Poerschke, Philip J. Moos
Journal: Cancer Research (2010)

Abstract Thioredoxin reductase (TR1) is a selenoprotein that is involved in cellular redox status control and deoxyribonucleotide biosynthesis. Many cancers, including lung, overexpress TR1, making it a potential cancer therapy target. TR1 is hypothesized to be involved in the mechanism of selenium in cancer etiology. Also of interest is the selenocompound methylseleninic acid (MSA). MSA is a known substrate of TR1 and previous work has shown that TR1 knockdown enhances MSA toxicity and redox status effects in human colon cancer cells compared to those with endogenous TR1 levels. However, it is unknown if TR1 knockdown produces similar effects of MSA in human lung cancer cells. To further elucidate the role of TR1 in the mechanism of MSA in lung cancer, a lentiviral microRNA delivery system to knockdown TR1 expression in A549 adenocarcinoma cells (A549 miR-TR1) was utilized. Redox status after 24 hr MSA treatment was assessed by measuring reactive oxygen species (ROS) generation, mitochondrial membrane depolarization, and total glutathione (GSH) concentration. Although the toxicity of MSA was not increased in A549 miR-TR1 cells at 24 hrs, changes in redox status parameters were observed. TR1 knockdown alone had no effect on mitochondrial membrane depolarization or ROS, but did increase ROS and mitochondrial membrane depolarization generated by MSA. Total GSH concentration was increased by TR1 knockdown alone, the majority of which was reduced glutathione. MSA decreased total GSH concentration and TR1 knockdown further enhanced this MSA-induced attenuation in total GSH. These results indicate the ability of TR1 to modulate the redox status effects of MSA in human lung cancer cells. Potential use of MSA as a cancer treatment in combination with TR1 inhibitors is also of interest. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2616.
Computed tomography in the investigation of dementia
Authors: B. Harris, M S Evans
Journal: BMJ (1983)

Dr Grant suggests that the use of sympathomimetic bronchodilators from nebulisers driven by compressed air may be responsible in part for the high New Zealand mortality rate.It is true that a compressor unit may be bought without a doctor's recommendation, but it is quite untrue that salbutamol solution may be obtained without a prescription in New Zealand, where the health care system is as highly developed as in the United Kingdom.We use nebulisers for chronic asthma and not for the self management of acute asthma attacks outside hospital.If we were to treat in hospital all patients with asthma severe enough to
Left Ventricular Wall Motion Abnormalities Induced by Squatting: A New Echocardiographic Stress Test for the Diagnosis of Coronary Artery Disease
Authors: P. Anthony N. Chandraratna, Rajiv Maraj, Ghasan Tabel, Arash Vahdat, Lalkrushna Malaviya
Journal: Journal of the American College of Cardiology (2005)
Hypermethylation of GpG islands in the promoter region of p15INK4b in acute promyelocytic leukemia represses p15INK4b expression and correlates with poor prognosis
Authors: L Teofili, M Martini, M Luongo, D Diverio, G Capelli, M Breccia, F Lo Coco, G Leone, L M Larocca
Journal: Leukemia (2003)
How important is time to treatment with primary percutaneous coronary intervention for acute myocardial infarction? Results from the CADILLAC trial
Authors: Bruce R. Brodie, David A. Cox, Thomas D. Stuckey, Mark Turco, Eulogio Garcia, John J. Griffin, Martin Fahy, James E. Tcheng, Cindy L. Grines, Roxana Mehran, Gregg W. Stone
Journal: Journal of the American College of Cardiology (2003)
Sympathoadrenal responses to acute and chronic hypoxia in the rat.
Authors: T S Johnson, J B Young, L Landsberg
Journal: Journal of Clinical Investigation (1983)

The sympathoadrenal responses to acute and chronic hypoxic exposure at 10.5 and 7.5% oxygen were determined in the rat. Cardiac norepinephrine (NE) turnover was used to assess sympathetic nervous system (SNS) activity, and urinary excretion of epinephrine (E) was measured as an index of adrenal medullary activity. The responses of the adrenal medulla and SNS were distinct and dependent upon the degree and duration of hypoxic exposure. Chronic hypoxia at 10.5% oxygen increased cardiac NE turnover by 130% after 3, 7, and 14 d of hypoxic exposure. Urinary excretion of NE was similarly increased over this time interval, while urinary E excretion was marginally elevated. In contrast, acute exposure to moderate hypoxia at 10.5% oxygen was not associated with an increase in SNS activity; in fact, decreased SNS activity was suggested by diminished cardiac NE turnover and urinary NE excretion over the first 12 h of hypoxic exposure, and by a rebound increase in NE turnover after reexposure to normal oxygen tension. Adrenal medullary activity, on the other hand, increased substantially during acute exposure to moderate hypoxia (2-fold increase in urinary E excretion) and severe hypoxia (greater than 10-fold). In distinction to the lack of effect of acute hypoxic exposure (10.5% oxygen), the SNS was markedly stimulated during the first day of hypoxia exposure at 7.5% oxygen, an increase that was sustained throughout at least 7 d at 7.5% oxygen. These results demonstrate that chronic exposure to moderate and severe hypoxia increases the activity of the SNS and adrenal medulla, the effect being greater in severe hypoxic exposure. The response to acute hypoxic exposure is more complicated; during the first 12 h of exposure at 10.5% oxygen, the SNS is not stimulated and appears to be restrained, while adrenal medullary activity is enhanced. Acute exposure to a more severe degree of hypoxia (7.5% oxygen), however, is associated with stimulation of both the SNS and adrenal medulla.
Intracardiac echocardiography during radiofrequency catheter ablation of cardiac arrhythmias in humans
Authors: Edward Chu, Jonathan M. Kalman, Michael A. Kwasman, John C.Y. Jue, Peter J. Fitzgerald, Laurence M. Epstein, Nelson B. Schiller, Paul G. Yock, Michael D. Lesh
Journal: Journal of the American College of Cardiology (1994)
Pregnancy and Travel: The Risks of Hepatitis and Scuba Diving-Reply
Authors: Michele Barry
Journal: JAMA (1989)

<h3>In Reply. —</h3> The information provided by these correspondents is pertinent and deserves emphasis. Dr Lettau notes the added risk that enterically transmitted non-A, non-B hepatitis poses for pregnant women, particularly during their third trimester, and the lack of protection offered by preparations of immune serum globulin from nonendemic areas. Hence, food and water precautions require additional emphasis for pregnant women. We understand that all pregnant women require testing for hepatitis B surface antigen during early pregnancy, and we would repeat testing following any potential exposures during pregnancy. Dr Mannino is correct on two counts. The oxygen tension values for umbilical artery and vein as they appear in both our article and quoted reference are reversed. As he indicated, it is a common error in the medical literature, and we perpetuated it. The correct units for hemoglobin concentrations are 8.5 g/dL or 85 g/L, not 0.085 g/L. The letters and
S75. KEYNOTE LECTURE: Basic concept for the understanding of cancer mediated immune rejection
Authors: F Marincola, E Wang
Journal: Journal for ImmunoTherapy of Cancer (2014)

Meeting abstracts Cancer is a multi-genic, complex biological phenomenon and its growth is affected by various categories of factors including the genetics of the host, the accumulating genetic alteration within cancer cells and environmental modifiers. Therefore, to identify the determinants of
Reversing Gears: Discontinuing Medication Therapy to Prevent Adverse Events
Authors: Amy Linsky, Steven R. Simon
Journal: JAMA Internal Medicine (2013)

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A Fluorescence <i>In situ</i> Hybridization Screen for E26 Transformation–Specific Aberrations: Identification of DDX5-ETV4 Fusion Protein in Prostate Cancer
Authors: Bo Han, Rohit Mehra, Saravana M. Dhanasekaran, Jindan Yu, Anjana Menon, Robert J. Lonigro, Xiaosong Wang, Yusong Gong, Lei Wang, Sunita Shankar, Bharathi Laxman, Rajal B. Shah, Sooryanarayana Varambally, Nallasivam Palanisamy, Scott A. Tomlins, Chandan Kumar-Sinha, Arul M. Chinnaiyan
Journal: Cancer Research (2008)

Recurrent gene fusions involving E26 transformation-specific (ETS) transcription factors ERG, ETV1, ETV4, or ETV5 have been identified in 40% to 70% of prostate cancers. Here, we used a comprehensive fluorescence in situ hybridization (FISH) split probe strategy interrogating all 27 ETS family members and their five known 5' fusion partners in a cohort of 110 clinically localized prostate cancer patients. Gene rearrangements were only identified in ETS genes that were previously implicated in prostate cancer gene fusions including ERG, ETV1, and ETV4 (43%, 5%, and 5%, respectively), suggesting that a substantial fraction of prostate cancers (estimated at 30-60%) cannot be attributed to an ETS gene fusion. Among the known 5' gene fusion partners, TMPRSS2 was rearranged in 47% of cases followed by SLC45A3, HNRPA2B1, and C15ORF21 in 2%, 1%, and 1% of cases, respectively. Based on this comprehensive FISH screen, we have made four noteworthy observations. First, by screening the entire ETS transcription factor family for rearrangements, we found that a large fraction of prostate cancers (44%) cannot be ascribed to an ETS gene fusion, an observation which will stimulate research into identifying recurrent non-ETS aberrations in prostate cancers. Second, we identified SLC45A3 as a novel 5' fusion partner of ERG; previously, TMPRSS2 was the only described 5' partner of ERG. Third, we identified two prostate-specific, androgen-induced genes, FLJ35294 and CANT1, as 5' partners to ETV1 and ETV4. Fourth, we identified a ubiquitously expressed, androgen-insensitive gene, DDX5, fused in frame with ETV4, leading to the expression of a DDX5-ETV4 fusion protein.