tbuckley/cabot-search huggingface dataset:
Neural Mechanisms of Anhedonia in Schizophrenia
Authors: Benedicto Crespo-Facorro, Sergio Paradiso, Nancy C. Andreasen, Daniel S. O'Leary, G. Leonard Watkins, Laura L. B. Ponto, Richard D. Hichwa
Journal: JAMA (2001)

Loss of the capacity to experience pleasure (anhedonia) is a core clinical feature of schizophrenia. Although functional imaging techniques have been successful in identifying the neural basis of cognitive impairments in schizophrenia, no attempts to date have been made to investigate neural systems underlying emotional disturbances.To study the neural basis of emotional processing in schizophrenia by exploring the pattern of brain responses to olfactory stimuli in patients and healthy volunteers.Positron emission tomographic study of patients with schizophrenia and healthy volunteers. Positron emission tomographic data were collected between July 21, 1995, and September 11, 1997, and data analyses were conducted in 1999-2001.The Mental Health Clinical Research Center at the University of Iowa, Iowa City.Sixteen healthy volunteers with a mean age of 29.5 years and 18 patients with schizophrenia and a mean age of 30.0 years.Areas of relative increase or decrease in regional cerebral blood flow, measured using positron emission tomography and the [(15)O]water method while participants performed an emotion-induction olfactory task to determine response to pleasant (vanillin) and unpleasant (4-methylvaleric acid) odors, compared between patients and healthy volunteers.Patients with schizophrenia subjectively experienced unpleasant odors in a manner similar to healthy volunteers but showed impairment in the experience of pleasant odors. The analysis of the regional cerebral blood flow revealed that patients failed to activate limbic/paralimbic regions (eg, insular cortex, nucleus accumbens, and parahippocampal gyrus) during the experience of unpleasant odors, recruiting a compensatory set of frontal cortical regions instead.Abnormalities in the complex functional interactions between mesolimbic and frontal regions may underlie emotional disturbances in schizophrenia.
Comparative Effectiveness Research: The Experience of the National Institute for Health and Clinical Excellence
Authors: Corinna Sorenson, Michael Drummond, Kalipso Chalkidou
Journal: Journal of Clinical Oncology (2012)

To assess the relevance of the experience of the National Institute for Health and Clinical Excellence (NICE) in the United Kingdom to the comparative effectiveness research (CER) initiative in the United States.The activities of NICE were reviewed to assess its experience in analytic methods, engagement with stakeholders, communication of findings, and implementation of recommendations.The main lessons for the United States from the experience of NICE relate to how the institute has gathered, synthesized, and used information on the clinical and cost effectiveness of health care interventions. The experience of NICE suggests that ways will have to be found to reconcile the differing stakeholder perspectives on the value of health care. Given the emphasis in the United States on being patient centered, there will be situations where patients' expectations for the provision of care far exceed that which payers feel should be made available on grounds of value for money. Explicit restrictions on access to care based on CER like those found in the United Kingdom are unlikely, but alternative solutions, such as value-based reimbursement, will need to be pursued if unnecessary expenditures are to be avoided. It will also be important that the CER initiative show some impact on the use of health care resources. The longer that NICE has been in existence in the United Kingdom, questions about its impact have been more frequently asked, given the resources devoted to its activities.Although there are distinct differences between the health systems of the United Kingdom and United States, lessons can be learned from examining the successes and challenges experienced by NICE.
Angiotensin II–Inducible Platelet-Derived Growth Factor-D Transcription Requires Specific Ser/Thr Residues in the Second Zinc Finger Region of Sp1
Authors: Nicole Y. Tan, Valerie C. Midgley, Mary M. Kavurma, Fernando S. Santiago, Xiao Luo, Ryan Peden, Roger G. Fahmy, Michael C. Berndt, Mark P. Molloy, Levon M. Khachigian
Journal: Circulation Research (2008)

Sp1, the first identified and cloned transcription factor, regulates gene expression via multiple mechanisms including direct protein–DNA interactions, protein–protein interactions, chromatin remodeling, and maintenance of methylation-free CpG islands. Sp1 is itself regulated at different levels, for example, by glycosylation, acetylation, and phosphorylation by kinases such as the atypical protein kinase C-ζ. Although Sp1 controls the basal and inducible regulation of many genes, the posttranslational processes regulating its function and their relevance to pathology are not well understood. Here we have used a variety of approaches to identify 3 amino acids (Thr668, Ser670, and Thr681) in the zinc finger domain of Sp1 that are modified by PKC-ζ and have generated novel anti-peptide antibodies recognizing the PKC-ζ–phosphorylated form of Sp1. Angiotensin II, which activates PKC-ζ phosphorylation (at Thr410) via the angiotensin II type 1 receptor, stimulates Sp1 phosphorylation and increases Sp1 binding to the platelet-derived growth factor-D promoter. All 3 residues in Sp1 (Thr668, Ser670, and Thr681) are required for Sp1-dependent platelet-derived growth factor-D activation in response to angiotensin II. Immunohistochemical analysis revealed that phosphorylated Sp1 is expressed in smooth muscle cells of human atherosclerotic plaques and is dynamically expressed together with platelet-derived growth factor-D in smooth muscle cells of the injured rat carotid artery wall. This study provides new insights into the regulatory mechanisms controlling the PKC-ζ–phospho-Sp1 axis and angiotensin II–inducible gene expression.
Role of thromboxane-A2 and cholinergic mechanisms in bronchoconstriction induced by cigarette smoke in guinea-pigs
Authors: K Matsumoto, H Aizawa, H Inoue, S Takata, M Shigyo, N Hara
Journal: European Respiratory Journal (1996)

Acute exposure to cigarette smoke provokes bronchoconstriction and increases the concentration of thromboxane (Tx) A2 in bronchoalveolar lavage (BAL) fluid. The purpose of this study was to investigate the role of TxA2 and cholinergic mechanisms in the airway response induced by exposure to cigarette smoke in guinea-pigs. Anaesthetized animals were exposed to 200 puffs of smoke for 10 min. The amount of Evans blue dye extravasated into the bronchial tissue was then measured BAL was performed to determine cell counts and the concentration of TxB2, a stable metabolite of TxA2. The effects of pretreatment with a Tx synthase inhibitor, OKY-046 (10 mg.kg-1), and/or atropine (1 mg.kg-1) were evaluated. Exposure to cigarette smoke caused significant bronchoconstriction (284 +/- 33% of baseline pulmonary resistance (RL)) and plasma extravasation (30.0 +/- 3.8 vs 16.8 +/- 2.6 ng.mg-1 of sham control; main bronchi). OKY-046 or atropine significantly inhibited the bronchoconstriction to a similar extent, without affecting the plasma extravasation. Combined use of these compounds had no additive effect. The cigarette smoke caused significant increase in TxB2 (48 +/- 10 vs 14 +/- 1 pg.mL-1 of sham control) in BAL fluid, which was abolished by OKY-046 but not by atropine. The cellularity in BAL fluid was not different among groups. These results suggest that the bronchoconstriction induced by cigarette smoke is partially mediated by thromboxane A2, which is dependent on a cholinergic pathway.
Human IgG antibody profiles differentiate between symptomatic patients with and without colorectal cancer
Authors: G Kijanka, S Hector, E W Kay, F Murray, R Cummins, D Murphy, B D MacCraith, J H M Prehn, D Kenny
Journal: Gut (2009)

<h3>Objective:</h3> Patients with cancer have antibodies against tumour antigens. Characterising the antibody repertoire may provide insights into aberrant cellular mechanisms in cancer development, ultimately leading to novel diagnostic or therapeutic targets. The aim of this study was to characterise the antibody profiles in patients whose symptoms warranted colonoscopy, to see if there was a difference in patients with and without colorectal cancer. <h3>Methods:</h3> Patients were recruited from a colonoscopy clinic. Individual serum samples from 43 patients with colorectal cancer and 40 patients with no cancer on colonoscopy were profiled on a 37 830 clone recombinant human protein array. Antigen expression was evaluated by quantitative reverse transcription-PCR and by immunohistochemistry on tissue microarrays. <h3>Results:</h3> Using a sex- and age-matched training set, 18 antigens associated with cancer and 4 associated with the absence of cancer (p&lt;0.05) were identified and confirmed. To investigate the mechanisms triggering antibody responses to these antigens, antigen expression was examined in normal colorectal mucosa and colorectal carcinoma of the same patients. The identified antigens showed cellular accumulation (p53), aberrant cellular expression (high mobility group B1 (HMGB1)) and overexpression (tripartite motif-containing 28 (TRIM28), p53, HMGB1, transcription factor 3 (TCF3), longevity assurance gene homologue 5 (LASS5) and zinc finger protein 346 (ZNF346)) in colorectal cancer tissue compared with normal colorectal mucosa. <h3>Conclusions:</h3> It is demonstrated for the first time that screening high-density protein arrays identifies unique antibody profiles that discriminate between symptomatic patients with and without colorectal cancer. The differential expression of identified antigens suggests their involvement in aberrant cellular mechanisms in cancer.
Single Cycle of Arsenic Trioxide–Based Consolidation Chemotherapy Spares Anthracycline Exposure in the Primary Management of Acute Promyelocytic Leukemia
Authors: Steven D. Gore, Ivana Gojo, Mikkael A. Sekeres, Lawrence Morris, Marcel Devetten, Katarzyna Jamieson, Robert L. Redner, Robert Arceci, Ibitayo Owoeye, Tianna Dauses, Esther Schachter-Tokarz, Robert E. Gallagher
Journal: Journal of Clinical Oncology (2010)

PURPOSE Event-free survival following all-trans-retinoic acid (ATRA) -based therapy for acute promyelocytic leukemia (APL) averages 70% at 5 years. While arsenic trioxide (ATO) can induce remissions in 95% of relapsed patients, few studies have addressed the integration of ATO into the primary management of APL. This study examines the efficacy of a single cycle of ATO-based consolidation therapy in a treatment regimen designed to decrease exposure to other cytotoxic agents. PATIENTS AND METHODS After induction with ATRA and daunorubicin (DRN), untreated patients with APL received 3 days of cytarabine and DRN followed by 30 doses of ATO beginning on day 8. Molecular remitters received 2 years of risk-based maintenance therapy. Results Forty-one of 45 patients receiving induction therapy achieved remission; four patients died (one before treatment was initiated). Thirty-seven patients received consolidation and maintenance; of these one patient relapsed (CNS) and one died in remission during maintenance therapy (hepatic sickle cell crisis). With a median follow-up of 2.7 years, estimated disease-free survival was 90%; overall survival for all patients was 88%. Despite a total anthracycline dose of only 360 mg/m(2), cardiac ejection fraction decreased by > or = 20% in 20% of patients. CONCLUSION These data, combined with other recent studies using ATO in the primary management of APL, demonstrate the important role that ATO can play in the primary management of this curable disease. Future studies should continue to focus on reducing the toxicity of treatment without increasing the relapse rate.
Liver Cell Adenoma-Reply
Authors: Janet K. Baum
Journal: JAMA (1976)

In Reply.—  Dr Cornish's statement of the apparent resolution of the hepatic cell adenoma following the return to normal of the liver scan after surgical clipping of the right hepatic artery is disturbing. In our experience, positive liver scans have only been found in patients who have had hemorrhage into the tumor. Several asymptomatic patients whose lesions were discovered during physical examinations or during surgery have all had normal scans. In light of our experience, we would assume that the reason the scan on Dr Cornish's patient is now normal is because of subsidence of bleeding into the lesion.  The patient should be examined angiographically, which, of course, will be difficult in view of the surgical clipping of the right hepatic artery. Possibly, portal venous studies via augmented superior mesenteric artery injections would demonstrate the lesion or at least the mass effect due to the lesion. Gray scale ultrasound might
Psychological predictors of injuries in circus artists: an exploratory study
Authors: Ian Shrier, Madeleine Hallé
Journal: British Journal of Sports Medicine (2010)

To explore the relationship between potential psychological risk factors and injury risk in circus artists.Historical cohort study.Cirque du Soleil training programme.Forty-seven circus artists training to become Cirque du Soleil artists.Artists completed the validated REST-Q questionnaire (19 domains) during their first 2 weeks of training.Injury risk ratio.Of the five a priori exposures of interest, injury, emotional exhaustion, self-efficacy and fatigue were associated with an increase in injury risk (risk ratios between 1.8 and 2.8), but Conflicts/Pressure was not (risk ratio=0.8). Of the several specific psychological aspects that are considered risk factors for injury, low self-efficacy had the strongest relationship.Most of the strong psychological risk factors for injuries previously identified in athletes also appear to be risk factors in circus artists.
miR-10a is aberrantly overexpressed in Nucleophosmin1 mutated acute myeloid leukaemia and its suppression induces cell death
Authors: Adam Bryant, Catalina A Palma, Vivek Jayaswal, Yee Wa Yang, Mark Lutherborrow, David DF Ma
Journal: Molecular Cancer (2012)

Abstract Background Acute myeloid leukaemia (AML) with nucleophosmin-1 ( NPM1 ) mutation is a major subtype of AML. The NPM1 mutation induces a myeloproliferative disorder, but evidence indicates that other insults are necessary for the development of AML. We utilised microRNA microarrays and functional assays to determine if microRNA dysregulation could be involved in the pathogenesis of in NPM1 mutated ( NPM1 mut )-AML. Results We used a stringent locked nucleic acid (LNA) based microRNA microarray platform to profile bone marrow samples of patients with normal karyotype AML. A panel of five microRNAs dichotomised AML patients according to their NPM1 mutational status. miR-10a, let-7b and let-7c were significantly over-expressed, while miR-130a and miR-335 were under-expressed in NPM1 mut -AML when compared to NPM1 wildtype -AML. Of these, miR-10a is the most differentially expressed in NPM1 mut -AML versus NPM1 wildtype -AML (&gt; 10 fold higher as confirmed by qRT-PCR). To investigate the functions of miR-10a, the OCI-AML3 cell line was utilised, which is the only commercially available cell line bearing NPM1 mut . OCI-AML3 cells were firstly demonstrated to have a similarly high miR-10a expression to primary NPM1 mut -AML patient samples. Inhibition of miR-10a expression by miRCURY LNA Inhibitors (Exiqon) in these cells resulted in increased cell death as assessed by MTS, cell cycle and Annexin-V assays and reduced clonogenic capacity, indicative of an involvement in leukaemic cell survival. In silico filtering of bioinformatically predicted targets of miR-10a identified a number of potential mRNA targets with annotated functions in haematopoiesis, cell growth and apoptosis. Lucferase reporter assays confirmed a number of these putative tumorogenic genes that are miR-10a suppressible including KLF4 and RB1CC1 . This provides a potential mechanism for the pathogenic role of miR-10a in NPM1 mut -AML. Conclusions This study provides, for the first time, in vitro evidence of a pro-survival role of miR-10a in NPM1 mut -AML, that it may contribute to the pathogenesis of NPM1 mut -AML and identifies putative tumorogenic targets.
Is Modulation of Sodium-Calcium Exchange a Therapeutic Option in Heart Failure?
Authors: Gerd Hasenfuss, Wolfgang Schillinger
Journal: Circulation Research (2004)

esides the sarcoplasmic reticulum (SR) Ca 2ϩ -ATPase (SERCA), the sarcolemmal Na ϩ -Ca 2ϩ exchanger (NCX) is the most important Ca 2ϩ transport protein responsible for maintaining the Ca 2ϩ balance of the myocyte.It catalyzes the transport of Ca 2ϩ across the membrane in exchange for Na ϩ in a reversible manner.Its activity is called "forward" when Na ϩ is transported inward and Ca 2ϩ outward and "reversed" when ions are transported in the opposite directions.The driving force of NCX depends on Na ϩ and Ca 2ϩ concentrations at either side of the plasma membrane and on the membrane potential.NCX is electrogenic and carries inward (depolarizing) current in forward mode and outward (repolarizing) current in reversed mode. 1 NCX consists of 9 transmembrane helices and a large cytoplasmic loop.This loop has been shown to contain Ca 2ϩ -and Na ϩ -binding regulatory sites, which are distinct from the transport sites.Thus, Na ϩ and Ca 2ϩ ions are both transport substrates and modulators of activity.At the N-terminal end of the cytoplasmic loop near the membrane-lipid interface, there is a 20-amino acid segment, designated the endogenous XIP region.This region is considered to function as an autoinhibitory domain that plays a central role in NCX regulation.2][3] More recently, it was shown that the Ca 2ϩ binding protein sorcin exerts stimulatory actions on NCX. 4 Altered expression and activity of the sarcolemmal NCX may play a key role for disturbed contractile function and arrhythmogenesis in hypertrophy and heart failure.It has become clear that disturbed excitation-contraction coupling attributable to altered SR Ca 2ϩ accumulation significantly contributes to heart failure pathophysiology. 3Three major factors seem to contribute to disturbed SR Ca 2ϩ accumulation in human heart failure: (1) increased leak of Ca 2ϩ through ryanodine receptors, (2) reduced SERCA activity, and (3) increased transsarcolemmal elimination of Ca 2ϩ by NCX.SR Ca 2ϩ accumulation depends on the activity of SERCA relative to transsarcolemmal Ca 2ϩ elimination by NCX.When protein
Anthracyclines Cause Endothelial Injury in Pediatric Cancer Patients: A Pilot Study
Authors: Amy Y. Chow, Clifford Chin, Gary Dahl, David N. Rosenthal
Journal: Journal of Clinical Oncology (2006)

The vascular endothelium plays a central role in the regulation of arterial vasomotor tone, releasing nitric oxide for vasodilation. Endothelial-dependent vasodilation can be assessed in vivo, using high resolution ultrasound to measure changes in diameter of the brachial artery. Animal studies have demonstrated that anthracyclines can damage the endothelium and impair the vasodilatory response of arteries; however, there are no comparable data in humans. This is a pilot study assessing endothelial toxicity from anthracyclines in pediatric cancer patients.Fourteen control patients and 14 cancer patients (4 to 21 years) were studied. Cancer patients had completed chemotherapy containing no less than 300 mg/m2 of anthracyclines 2 to 60 months before study. Brachial artery diameters were measured at rest and 1 minute after blood pressure cuff occlusion. Brachial artery reactivity (BAR) was calculated as percent change between baseline and after cuff deflation measurements. Results were compared using unpaired, two-tailed t-test.Baseline characteristics, including age, percentage of females, blood pressure, and resting vessel diameters were similar between the two groups. BAR in the controls averaged 6.7% with a standard deviation (SD) of 3.3%, while BAR in patients receiving anthracyclines averaged 3.8% with an SD of 3.4%, demonstrating a significant decrease (P < .05) in vasomotor reactivity in the treated group.These results suggest that anthracyclines cause impaired endothelial function, an important and newly recognized toxicity. Since endothelial dysfunction is an early event in atherogenesis, there may be important clinical implications from these findings. Further study is required to confirm these preliminary results in a larger cohort.
Role of nitric oxide in the neural control of cardiovascular function
Authors: J Zanzinger
Journal: Cardiovascular Research (1999)

The discovery in 1990 that nitric oxide (NO) acts as a neuromodulator within the central and peripheral nervous system triggered intensive research which considerably extended our understanding how this factor regulates cardiovascular functions. In addition to its direct effects on blood vessels NO has additional targets at all levels of the neural control of circulation. When not scavenged by hemoglobin, NO is relatively stable and diffuses over large distances (>500 μm) so that one NO-producing cell can influence several thousends of adjacent cells in vivo. In different brain regions, NO and its metabolites have excitatory as well as inhibitory effects. The modulation of autonomic functions by these factors is therefore highly complex and often variable between the different levels from the brain to postganglionic nerve endings. This review is focused on the available evidence derived from animal studies and will summarize the current discussion about (i) the modulation of the generation of sympathetic and parasympathetic activities within the brain stem by NO; (ii) the actions of NO on cardiovascular reflexes and (iii) the role of NO as a modulator of autonomic functions within the target organs. Finally, the available evidence from human studies and some pathophysiological implications of altered NO-mediated modulation of the neural control of circulation will be discussed.