tbuckley/cabot-search huggingface dataset:
Acute Myelomonocytic Leukemia After Radioiodine Therapy of Hyperthyroidism
Authors: John E. Johnson
Journal: JAMA (1962)

THE COMPLICATIONS of radioactive iodine therapy of hyperthyroidism are few. A theoretically possible complication is the occurrence of radiation-induced leukemia. This has probably followed x-ray therapy of ankylosing spondylitis and after the high-dosage radioactive iodine therapy of thyroid cancer. In an attempt to answer the question whether the lower dosage of radioactive iodine that is used in treatment of hyperthyroidism may be incriminated in leukemogenesis, Pochin analyzed data from 60,000 patients and found 18 cases of leukemia occurring during the 222,000 patient years of follow-up. This figure compared with an estimated  incidence of 21 cases that might have occurred by chance. Because the number of cases in both the observed and expected series is small, it would be desirable to extend such observations to a larger number of patients. If such a relationship does exist, it is obviously important to define as early as possible the magnitude of the
Regulation of CBP-Mediated Transcription by Neuronal Calcium Signaling
Authors: Shu-Ching Hu, John Chrivia, Anirvan Ghosh
Journal: Neuron (1999)

The transcription factor CREB is involved in mediating many of the long-term effects of activity-dependent plasticity at glutamatergic synapses. Here, we show that activation of NMDA receptors and voltage-sensitive calcium channels leads to CREB-mediated transcription in cortical neurons via a mechanism regulated by CREB-binding protein (CBP). Recruitment of CBP to the promoter is not sufficient for transactivation, but calcium influx can induce CBP-mediated transcription via two distinct transactivation domains. CBP-mediated transcription is stimulus strength–dependent and can be induced by activation of CaM kinase II, CaM kinase IV, and protein kinase A, but not by activation of the Ras–MAP kinase pathway. These observations indicate that CBP can function as a calcium-sensitive transcriptional coactivator that may act as a regulatory switch for glutamate-induced CREB-mediated transcription.
Association and interaction analyses of eight genes under asthma linkage peaks
Authors: M. A. R. Ferreira, Z. Z. Zhao, S. F. Thomsen, M. James, D. M. Evans, P. E. Postmus, K. O. Kyvik, V. Backer, D. I. Boomsma, N. G. Martin, G. W. Montgomery, D. L. Duffy
Journal: Allergy (2009)

Background: Linkage studies have implicated the 2q33, 9p21, 11q13 and 20q13 regions in the regulation of allergic disease. The aim of this study was to test genetic variants in candidate genes from these regions for association with specific asthma traits. Methods: Ninety‐five single nucleotide polymorphisms (SNP) located in eight genes ( CD28 , CTLA4 , ICOS , ADAM23 , ADAMTSL1 , MS4A2 , CDH26 and HRH3 ) were genotyped in &gt;5000 individuals from Australian ( n = 1162), Dutch ( n = 99) and Danish ( n = 303) families. Traits tested included doctor‐diagnosed asthma, atopy, airway obstruction, total serum immunoglobulin (Ig) E levels and eosinophilia. Association was tested using both multivariate and univariate methods, with gene‐wide thresholds for significance determined through simulation. Gene‐by‐gene and gene‐by‐environment analyses were also performed. Results: There was no overall evidence for association with seven of the eight genes tested when considering all genetic variation assayed in each gene. The exception was MS4A2 on chromosome 11q13, which showed weak evidence for association with IgE (gene‐wide P &lt; 0.05, rs502581). There were no significant gene‐by‐gene or gene‐by‐environment interaction effects after accounting for the number of tests performed. Conclusions: The individual variants genotyped in the 2q33, 9p21 and 20q13 regions do not explain a large fraction of the variation in the quantitative traits tested or have a major impact on asthma or atopy risk. Our results are consistent with a weak effect of MS4A2 polymorphisms on the variation of total IgE levels.
Improvement of sublingual immunotherapy efficacy with a mucoadhesive allergen formulation
Authors: Alain Razafindratsita, Nathalie Saint-Lu, Laurent Mascarell, Nathalie Berjont, Thierry Bardon, Didier Betbeder, Laurence Van Overtvelt, Philippe Moingeon
Journal: Journal of Allergy and Clinical Immunology (2007)
Ghrelin receptor mutations -- too little height and too much hunger
Authors: Birgitte Holst, Thue W Schwartz
Journal: Journal of Clinical Investigation (2006)

The ghrelin receptor is known from in vitro studies to signal in the absence of the hormone ghrelin at almost 50% of its maximal capacity. But, as for many other 7-transmembrane receptors, the in vivo importance of this ligand-independent signaling has remained unclear. In this issue of the JCI, Pantel et al. find that a natural mutation in the ghrelin receptor, Ala204Glu, which is associated with a selective loss of constitutive activity without affecting ghrelin affinity, potency, or efficacy, segregates in 2 families with the development of short stature (see the related article beginning on page 760). By combination of the observations from this study with those related to the phenotype of subjects carrying another natural ghrelin receptor mutation, Phe279Leu, having identical molecular-pharmacological properties, it is proposed that selective lack of ghrelin receptor constitutive signaling leads to a syndrome characterized not only by short stature, but also by obesity that apparently develops during puberty.
Mechanisms of hypergammaglobulinemia and impaired antigen-specific humoral immunity in HIV-1 infection
Authors: Angelo De Milito, Anna Nilsson, Kehmia Titanji, Rigmor Thorstensson, Elisabet Reizenstein, Mitsuo Narita, Sven Grutzmeier, Anders Sönnerborg, Francesca Chiodi
Journal: Blood (2003)
Focused Deterrence and the Prevention of Violent Gun Injuries: Practice, Theoretical Principles, and Scientific Evidence
Authors: Anthony A. Braga, David L. Weisburd
Journal: Annual Review of Public Health (2014)

Focused deterrence strategies are a relatively new addition to a growing portfolio of evidence-based violent gun injury prevention practices available to policy makers and practitioners. These strategies seek to change offender behavior by understanding the underlying violence-producing dynamics and conditions that sustain recurring violent gun injury problems and by implementing a blended strategy of law enforcement, community mobilization, and social service actions. Consistent with documented public health practice, the focused deterrence approach identifies underlying risk factors and causes of recurring violent gun injury problems, develops tailored responses to these underlying conditions, and measures the impact of implemented interventions. This article reviews the practice, theoretical principles, and evaluation evidence on focused deterrence strategies. Although more rigorous randomized studies are needed, the available empirical evidence suggests that these strategies generate noteworthy gun violence reduction impacts and should be part of a broader portfolio of violence prevention strategies available to policy makers and practitioners.
MicroRNAs: components of an integrated system controlling cardiac development, physiology, and disease pathogenesis
Authors: G. Condorelli, S. Dimmeler
Journal: Cardiovascular Research (2008)

See reviews in this series by Fazi and Nervi,21 Thum et al. ,22 Yang et al. ,23 and Urbich et al. 24 

Protein-encoding sequences comprise <1.5% of the human genome.1 Nevertheless, a considerable fraction (∼90%) of the genome is effectively transcribed.2 Therefore, most of the transcriptional output of the genome of higher organisms seems to consist of non-coding (nc) RNAs, i.e. RNA that is not translated into a protein end product.3 It is now clear that much of this genomic output is not just transcriptional background noise of ‘junk’ DNA but an intricate RNA-based network constituting a level of regulation that appears as important as posttranscriptional protein modification. Only a limited number of ncRNA species predominantly maintaining basic biochemical processes, such as ribosomal RNA and transfer RNA, have been analysed in depth, but other types of ncRNAs have now been identified and are being studied.4 These ncRNAs regulate the gene expression process at many of its steps, from the epigenetic level down to translation, through a variety of mechanisms ( Figure 1 ).5 ncRNA has also been implicated in surprising areas, such as the integrity of cellular structure,6 and many other fascinating functions probably await discovery.



Figure 1 
Outline of some ncRNA functions. The central dogma of the flow …
Improved genome assembly and evidence-based global gene model set for the chordate Ciona intestinalis: new insight into intron and operon populations
Authors: Yutaka Satou, Katsuhiko Mineta, Michio Ogasawara, Yasunori Sasakura, Eiichi Shoguchi, Keisuke Ueno, Lixy Yamada, Jun Matsumoto, Jessica Wasserscheid, Ken Dewar, Graham B Wiley, Simone L Macmil, Bruce A Roe, Robert W Zeller, Kenneth EM Hastings, Patrick Lemaire, Erika Lindquist, Toshinori Endo, Kohji Hotta, Kazuo Inaba
Journal: Genome biology (2008)

Abstract Background The draft genome sequence of the ascidian Ciona intestinalis , along with associated gene models, has been a valuable research resource. However, recently accumulated expressed sequence tag (EST)/cDNA data have revealed numerous inconsistencies with the gene models due in part to intrinsic limitations in gene prediction programs and in part to the fragmented nature of the assembly. Results We have prepared a less-fragmented assembly on the basis of scaffold-joining guided by paired-end EST and bacterial artificial chromosome (BAC) sequences, and BAC chromosomal in situ hybridization data. The new assembly (115.2 Mb) is similar in length to the initial assembly (116.7 Mb) but contains 1,272 (approximately 50%) fewer scaffolds. The largest scaffold in the new assembly incorporates 95 initial-assembly scaffolds. In conjunction with the new assembly, we have prepared a greatly improved global gene model set strictly correlated with the extensive currently available EST data. The total gene number (15,254) is similar to that of the initial set (15,582), but the new set includes 3,330 models at genomic sites where none were present in the initial set, and 1,779 models that represent fusions of multiple previously incomplete models. In approximately half, 5'-ends were precisely mapped using 5'-full-length ESTs, an important refinement even in otherwise unchanged models. Conclusion Using these new resources, we identify a population of non-canonical (non-GT-AG) introns and also find that approximately 20% of Ciona genes reside in operons and that operons contain a high proportion of single-exon genes. Thus, the present dataset provides an opportunity to analyze the Ciona genome much more precisely than ever.
Evaluation of Polyneuropathy Markers in Type 1 Diabetic Kidney Transplant Patients and Effects of Islet Transplantation
Authors: Ubaldo Del Carro, Paolo Fiorina, Stefano Amadio, Luisa De Toni Franceschini, Alessandra Petrelli, Stefano Menini, Filippo Martinelli Boneschi, Stefania Ferrari, Giuseppe Pugliese, Paola Maffi, Giancarlo Comi, Antonio Secchi
Journal: Diabetes Care (2007)

The purpose of this study was to evaluate whether islet transplantation may stabilize polyneuropathy in uremic type 1 diabetic patients (end-stage renal disease [ESRD] and type 1 diabetes), who received a successful islet-after-kidney transplantation (KI-s).Eighteen KI-s patients underwent electroneurographic tests of sural, peroneal, ulnar, and median nerves: the nerve conduction velocity (NCV) index and amplitudes of both sensory action potentials (SAPs) and compound motor action potentials (CMAPs) were analyzed longitudinally at 2, 4, and 6 years after islet transplantation. Skin content of advanced glycation end products (AGEs) and expression of their specific receptors (RAGE) were also studied at the 4-year follow-up. Nine patients with ESRD and type 1 diabetes who received kidney transplantation alone (KD) served as control subjects.The NCV score improved in the KI-s group up to the 4-year time point (P = 0.01 versus baseline) and stabilized 2 years later, whereas the same parameter did not change significantly in the KD group throughout the follow-up period or when a cross-sectional analysis between groups was performed. Either SAP or CMAP amplitudes recovered in the KI-s group, whereas they continued worsening in KD control subjects. AGE and RAGE levels in perineurium and vasa nervorum of skin biopsies were lower in the KI-s than in the KD group (P < 0.01 for RAGE).Islet transplantation seems to prevent long-term worsening of polyneuropathy in patients with ESRD and type 1 diabetes who receive islets after kidney transplantation. No statistical differences between the two groups were evident on cross-sectional analysis. A reduction in AGE/RAGE expression in the peripheral nervous system was shown in patients receiving islet transplantation.
Cardiac Resynchronization Therapy for Heart Failure
Authors: Clyde W. Yancy, Giovanni Filardo
Journal: Circulation (2009)

I n the current issue of Circulation, Anand and colleagues representing the COMPANION (The Comparison of Medical Therapy, Pacing and Defibrillation in Heart Failure) Investigators have brought forward compelling data that emphasize the substantial morbidity benefit of cardiac resynchronization therapy (CRT) in patients with moderately severe to severe heart failure.Unlike other studies that have reported reductions in heart failure hospitalizations, Anand et al have accounted for the competing risk of death and variations in follow-up time and surmised that CRT resulted in 44% (optimal pharmacological therapy plus CRT [CRT-P]) and 41% (optimal pharmacological therapy plus CRT with defibrillator [CRT-D]) reductions in heart failure-related hospitalizations.Remarkably, the benefit was seen within days to weeks and was a sustained effect throughout the trial. 1 By our calculations using the reported heart failure hospitalization rates (0.73 for optimal pharmacological therapy [OPT], 0.43 for CRT-D, and 0.41 for CRT-P), the number needed to treat with CRT to reduce 1 hospitalization is Ͻ4.This is a remarkable benefit for any evidence-based heart failure therapy.These data are sufficiently compelling that when aggregated with the known survival benefits ascribed to CRT, at least some of the residual concerns about efficacy for this device-based intervention should be assuaged.On the basis of these findings, the time may now have come to fundamentally change practice and to more avidly adhere to already extant class I indications for CRT in patients with class III or IV heart failure, with a prolonged QRS, and who are already on appropriate background medical therapy.
Airway smooth muscle thickness in asthma is related to severity but not duration of asthma
Authors: A. L. James, T. R. Bai, T. Mauad, M. J. Abramson, M. Dolhnikoff, K. O. McKay, P. S. Maxwell, J. G. Elliot, F. H. Green
Journal: European Respiratory Journal (2009)

Asthma is characterised by an increased airway smooth muscle (ASM) area (ASM area ) within the airway wall. The present study examined the relationship of factors including severity and duration of asthma to ASM area . The perimeter of the basement membrane (PBM) and ASM area were measured on transverse sections of large and small airways from post mortem cases of fatal (n = 107) and nonfatal asthma (n = 37) and from control subjects (n = 69). The thickness of ASM (ASM area /PBM) was compared between asthma groups using multivariate linear regression. When all airways were considered together, ASM area /PBM (in millimetres) was increased in nonfatal (median 0.04; interquartile range 0.013–0.051; p = 0.034) and fatal cases of asthma (0.048; 0.025–0.078; p&lt;0.001) compared with controls (0.036; 0.024–0.042). Compared with cases of nonfatal asthma, ASM area /PBM was greater in cases of fatal asthma in large (p&lt;0.001) and medium (p&lt;0.001), but not small, airways. ASM area /PBM was not related to duration of asthma, age of onset of asthma, sex or smoking. No effect due to study centre, other than that due to sampling strategy, was found. The thickness of the ASM layer is increased in asthma and is related to the severity of asthma but not its duration.
A pilot study of CPAP therapy for excessive dynamic airway collapse during acute exacerbation of COPD
Authors: Yee Tung (Eric) Kuo, Kenneth Lau, Garun Hamilton, Eunice Dai, Paul Leong, Philip Bardin
Journal: European Respiratory Journal (2014)

Background:  Excessive dynamic airway collapse (EDAC) occurs in expiration when the posterior wall of the trachea bulges forward causing ≥ 50% cross sectional area reduction. EDAC can be diagnosed with four-dimensional dynamic volume 320-slice multi-detector computed tomography (4D-CT) and has been reported to occur in 20% of patients with COPD. Whether EDAC persists in stable COPD or occurs predominantly during exacerbations is unknown. Overall effectiveness of CPAP in EDAC has also not been assessed.   Aims:  To determine whether CPAP therapy reduced EDAC in patients with acute exacerbation of COPD (AECOPD) and if EDAC persisted after recovery from AECOPD.   Methods:  Patients with AECOPD requiring hospitalization (n = 11) were recruited. 4D-CT of the larynx and trachea (2-4 mSv) was performed within 48 hours of admission and repeated immediately after with 10-12cmH2O CPAP. CT was repeated at 6-8 weeks post discharge (without CPAP). EDAC was diagnosed if expiratory tracheal area was reduced by ≥ 50%.   Results:  Of the 11 patients recruited, four had EDAC detected. EDAC severity ranged from 60-64% (median = 63.5%). EDAC resolved with CPAP in all four patients (median narrowing = 39.5% [29%-49%]). EDAC was not evident in the three patients who completed follow-up CT (one CT not done).   Conclusions:  EDAC in AECOPD can be improved by CPAP. Larger studies are warranted to further evaluate the functional significance of EDAC and clinical benefits of CPAP treatment.
The Clinical Discovery of Imipramine
Authors: Walter A. Brown, Maria Rosdolsky
Journal: American Journal of Psychiatry (2015)

The major classes of psychotropic drugs were introduced in an extraordinary decade of discovery between the late 1940s and late 1950s. In the present climate of pessimism about the absence of new drug development, it may be instructive to look back at the research methods used during that era. The study that identified the first antidepressant is a case in point. It was conducted by Roland Kuhn, a Swiss psychiatrist working in a remote psychiatric hospital. Kuhn, like the other pioneering researchers of his day, was given access to new drug entities, and the method he used to discover their clinical effects was open-minded, exploratory, comprehensive, clinical observation. The paper that reported the results of his study has not been available in English, but because of its historical significance and because Kuhn's achievement stands in such contrast to the present impasse in drug development, the authors thought that it might be informative to read about his discovery in his own words. Accordingly, one of the authors (M.R.) translated the paper into English, and they now present excerpts of that translation with the intent of encouraging reevaluation of contemporary approaches to drug discovery. By today's clinical research standards, Kuhn's method of unfettered, exploratory, clinical observation was substandard, haphazard, even messy. Yet it produced a major breakthrough—the discovery that a drug can alleviate depression—that has had a lasting impact on the treatment of depression and on the development of antidepressant drugs. Kuhn's experience might usefully inform our strategies of drug development.
Home or Hospital Births?
Authors: G. David Adamson
Journal: JAMA (1980)

Advocates of home birth cite psychological and medical benefits in their demand for a different approach to birthing procedures. Opponents emphasize the risks of this approach and point to improved outcomes through medical progress available only in hospitals, as well as to recent, less positive European attitudes toward home births. A review of the literature shows that present data are limited and do not conclusively support either opinion. It is essential that the medical profession become actively involved in an objective analysis of the merits and deficiencies of home and hospital birth settings. This participation should ensure that new approaches to birth will maintain the highest possible standards in maternal, fetal, and neonatal welfare. (<i>JAMA</i>243:1732-1736, 1980)
Nurses' Experiences with Hospice Patients Who Refuse Food and Fluids to Hasten Death
Authors: Linda Ganzini, Elizabeth R. Goy, Lois L. Miller, Theresa A. Harvath, Ann Jackson, Molly A. Delorit
Journal: New England Journal of Medicine (2003)

Voluntary refusal of food and fluids has been proposed as an alternative to physician-assisted suicide for terminally ill patients who wish to hasten death. There are few reports of patients who have made this choice.
Fluocinolone Acetonide Intravitreal Implant for Diabetic Macular Edema: A 3-Year Multicenter, Randomized, Controlled Clinical Trial
Authors: P. Andrew Pearson, Timothy L. Comstock, Michael Ip, David Callanan, Lawrence S. Morse, Paul Ashton, Brian Levy, Eric S. Mann, Dean Eliott
Journal: Ophthalmology (2011)
Randomised controlled trial of routine individual feedback to improve rationality and reduce numbers of test requests
Authors: R.A.G. Winkens, P. Pop, A.M.A. Bugter-Maessen, R.P.T.M. Grol, A.D.M. Kester, G.H.M.I. Beusmans, J.A. Knottnerus
Journal: The Lancet (1995)
A Potent Combination of the Novel PI3K Inhibitor, GDC-0941, with Imatinib in Gastrointestinal Stromal Tumor Xenografts: Long-Lasting Responses after Treatment Withdrawal
Authors: Giuseppe Floris, Agnieszka Wozniak, Raf Sciot, Haifu Li, Lori Friedman, Thomas Van Looy, Jasmien Wellens, Peter Vermaelen, Christophe M. Deroose, Jonathan A. Fletcher, Maria Debiec-Rychter, Patrick Schöffski
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Oncogenic signaling in gastrointestinal stromal tumors (GIST) is sustained via PI3K/AKT pathway. We used a panel of six GIST xenograft models to assess efficacy of GDC-0941 as single agent or in combination with imatinib (IMA). Experimental Design: Nude mice (n = 136) were grafted bilaterally with human GIST carrying diverse KIT mutations. Mice were orally dosed over four weeks, grouped as follows: (A) control; (B) GDC-0941; (C) imatinib, and (D) GDC+IMA treatments. Xenografts regrowth after treatment discontinuation was assessed in groups C and D for an additional four weeks. Tumor response was assessed by volume measurements, micro-PET imaging, histopathology, and immunoblotting. Moreover, genomic alterations in PTEN/PI3K/AKT pathway were evaluated. Results: In all models, GDC-0941 caused tumor growth stabilization, inhibiting tumor cell proliferation, but did not induce apoptosis. Under GDC+IMA, profound tumor regression, superior to either treatment alone, was observed. This effect was associated with the best histologic response, a nearly complete proliferation arrest and increased apoptosis. Tumor regrowth assays confirmed superior activity of GDC+IMA over imatinib; in three of six models, tumor volume remained reduced and stable even after treatment discontinuation. A positive correlation between response to GDC+IMA and PTEN loss, both on gene and protein levels, was found. Conclusion: GDC+IMA has significant antitumor efficacy in GIST xenografts, inducing more substantial tumor regression, apoptosis, and durable effects than imatinib. Notably, after treatment withdrawal, tumor regression was sustained in tumors exposed to GDC+IMA, which was not observed under imatinib. Assessment of PTEN status may represent a useful predictive biomarker for patient selection. Clin Cancer Res; 19(3); 620–30. ©2012 AACR.