tbuckley/cabot-search huggingface dataset:
RNA Splicing
Authors: Maarten M.G. van den Hoogenhof, Yigal M. Pinto, Esther E. Creemers
Journal: Circulation Research (2016)

RNA splicing represents a post-transcriptional mechanism to generate multiple functional RNAs or proteins from a single transcript. The evolution of RNA splicing is a prime example of the Darwinian function follows form concept. A mutation that leads to a new mRNA (form) that encodes for a new functional protein (function) is likely to be retained, and this way, the genome has gradually evolved to encode for genes with multiple isoforms, thereby creating an enormously diverse transcriptome. Advances in technologies to characterize RNA populations have led to a better understanding of RNA processing in health and disease. In the heart, alternative splicing is increasingly being recognized as an important layer of post-transcriptional gene regulation. Moreover, the recent identification of several cardiac splice factors, such as RNA-binding motif protein 20 and SF3B1, not only provided important insight into the mechanisms underlying alternative splicing but also revealed how these splicing factors impact functional properties of the heart. Here, we review our current knowledge of alternative splicing in the heart, with a particular focus on the major and minor spliceosome, the factors controlling RNA splicing, and the role of alternative splicing in cardiac development and disease.
Regulation of Cell Volume in Health and Disease
Authors: M L McManus, K B Churchwell, K Strange
Journal: New England Journal of Medicine (1995)

Maintenance of a constant volume in the face of extracellular and intracellular osmotic perturbations is a critical problem faced by all cells. Most cells respond to swelling or shrinkage by activating specific metabolic or membrane-transport processes that return cell volume to its normal resting state. These processes are essential for the normal function and survival of cells. This article will outline the cellular and molecular events underlying cell-volume homeostasis and discuss their relevance to medical practice. Fundamentals of Cell-Volume Regulation Meeting Osmotic Challenges Water is in thermodynamic equilibrium across the plasma membrane. In other words, the osmotic concentrations of cytoplasmic . . .
P142 Reduced all cause Healthcare Utilisation after Breathing Retraining for Dysfunctional Breathing
Authors: FC Thomson, DJ Ford
Journal: Thorax (2015)

<h3>Introduction</h3> There are few controlled studies to prove the effectiveness of breathing retraining in the management of dysfunctional breathing (Cochrane 2013) and only one observational study which shows a reduction in Emergency Room attendance (Hagman 2011) as a measure of the efficacy widely reported in clinical practice. <h3>Method</h3> Using all consecutive unselected patients referred to a single Respiratory Physiotherapy Unit with 2 experienced practitioners between April 2012 – April 2013, a historical control was used to examine the healthcare utilisation of this group. The incidence of all cause new Out Patient referrals, A+E visits, and admissions in the six month period prior to treatment was compared to the six months after the study period. Extraction of data was by review of notes and computerised search of hospital events with anonymised patient data. In addition to this information on baseline characteristics, response to treatment, and comorbidities were also examined. <h3>Results</h3> 67 patients were recorded, 2 were duplicate referrals and excluded from further analysis. The majority were referred by the Respiratory Service, but 27 by General Practice and senior nurses. Mean age was 58 (SD 15.6) and male to female ratio 30 to 37 respectively. 93% had one or more comorbidities, the most frequent being asthma in 49%. 58 patients attended for breathing retraining with an average Nijmegen score of 26.31 (SD 10.28). In the 6 months after physiotherapy, new outpatient referrals fell by 56% (from 70 to 31), A+E visits fell by 17% (30 to 25) but admissions rose by 35% (20 to 27). The overall reduction of secondary care visits was 31% (120 to 83). Exploratory analysis using Wilcoxon matched-pairs signed rank test showed statistical significance in the outpatient referral group only (p &lt; 0.01). <h3>Conclusion</h3> While this is crude data based on limited numbers in a single site, the size of effect is noteworthy, suggesting efficacy of intervention. Healthcare utilisationwasnot restricted to Respiratory presentation, in keeping with the multi-symptomatic nature of this condition. The rise in admissions is in contrast but did not relate to respiratory symptoms in this ageing population over a 24 month period. Further study is warranted. <h3>References</h3> 1 Jones M, Harvey A, Marston L. <i>et al.</i> Breathing exercises for dysfunctional breathing/hyperventilation syndrome in adults.<i> Cochrane Database Syst Rev</i>. 2013;<b>5</b>:CD009041 2 Hagman C, Janson C, Emtner M. <i>et al.</i> Breathing retraining - a five-year follow-up of patients with dysfunctional breathing.<i> Respir Med</i>. 2011;<b>105</b>:1153–9
Treating hepatitis B virus/hepatitis C virus coinfected patients with direct‐acting hepatitis C virus antivirals only is not safe
Authors: Resat Ozaras, Mustafa Sunbul, Mehmet Parlak, Hurrem Bodur, Hakan Leblebicioglu
Journal: Hepatology (2016)

Direct-acting antivirals (DAAs) enabled cure of chronic hepatitis C (CHC) in high rates with acceptable tolerability. Hepatitis B (HBV) and C virus (HCV) coinfected patients may not benefit if only CHC is treated with DAAs. We reviewed the medical literature and noticed 4 cases (Table 1). Age (years) HBsAg(+) HBeAg (−) HBV DNA 2.5 log copies/mL HBsAg (+) HBV DNA 2,300 IU/mL Genotype 1a HCV RNA 1,300,000 IU/mL HBsAg (−) Anti-HBs (−) Anti-HBcIgG(+) HBV-DNA <20 IU/m HBsAg (−) Anti-HBs (−) Anti-HBcIgG(+) HBV DNA (−) Takayama et al. described an HBV reactivation after use of daclatasvir and asunaprevir on day 15 with alanine aminotransferase (ALT) of 237 IU/mL.1 Baseline HBV-DNA of 2.5 log copies/mL increased to 7 logs copies/mL. Entecavir initiated after day 50 controlled HBV flare. Collins et al. described 2 coinfected patients2: Eight weeks after sofosbuvir and simeprevir, ALT increased to 1,495 IU/L and total bilirubin to 12.2 mg/dL. Tenofovir/emtricitabine combination controlled HBV flare. Another patient, a 57-year-old male, had HCV and isolated anti-HBcIgG (hepatitis B core immunoglobulin G antibody) positivity. At week 2 of sofosbuvir and simeprevir treatment, HBV DNA increased to 353 IU/mL and in week 4 to 11,255 IU/mL. Tenofovir was added for HBV reactivation. Another report described liver failure after using HCV drugs for a coinfected patient.3 A 59-year-old female had HCV and isolated anti-HBcIgG positivity. She was given simeprevir, sofosbuvir, and ribavirin. In week 11, ALT increased to 2,263 U/L, total bilirubin was 9.1 mg/dL, and international normalized ratio (INR) was 1.9. Repeated testing showed hepatitis B surface antigen (HBsAg) positive and HBV DNA 29,000,000 IU/mL. Tenofovir was initiated on the third day of HBV reactivation. However, she became encephalopathic with a rising INR and underwent liver transplantation. HBV/HCV coinfection usually follows a course of HCV dominance. The HCV core inhibits HBV replication and HBsAg expression. Secretion of the HBV and viral proteins is significantly reduced in the presence of HCV core or nonstructural 2 (NS2) protein.4 Because DAAs have no effect on HBV replication, the flare is observed weeks after initiation of therapy. Limited experience with HBV/HCV coinfected patients shows that either HBV-DNA levels should be monitored closely or HCV drugs should be used combined with HBV treatment. Close monitoring and early recognition of reactivation may prevent severe flare or liver failure. Resat Ozaras, M.D.1 Mustafa Sunbul, M.D.2 Mehmet Parlak, M.D.3 Hurrem Bodur, M.D.4 Hakan Leblebicioglu, M.D.2 1Department of Infectious Diseases Istanbul University Cerrahpasa Medical School Istanbul, Turkey 2Department of Infectious Diseases Ondokuz Mayis University Medical School Samsun, Turkey 3Department of Infectious Diseases Ataturk University Medical School Erzurum, Turkey 4Ankara Education and Teaching Hospital Ankara, Turkey
Audit Commission tackles anaesthetic services
Authors: J. E Arrowsmith, R. Alexander, G. d. L. Dear, T. J. Gan, R. P Hill, A. Olufolabi, I. C Sanderson, A. J Soppitt, D N Robinson, V Chopra, D W Green
Journal: BMJ (1998)

Editor—We read with interest the articles1,2 that you recently published in response to the Audit Commission’s Anaesthesia under Examination,3 which revisits the topic of nurse anaesthetists. We trained as anaesthetists in the United Kingdom but now work in the United States. 

Nurse anaesthetists in the United States always work under the direction of a physician and, despite our initial reservations, we have all been pleasantly surprised by the experience of working with this highly qualified group of professionals. Minimal requirements for entry to the training programmes of two to three years are a nursing or basic science college degree and one year’s experience in critical care nursing. Fear of unemployment in recent years has produced a sharp fall in applications to anaesthesia residency programmes.4 Most programmes have downsized, and a few have closed altogether. Rather than appoint more consultants, many hospitals have recruited nurse anaesthetists to meet their commitments—an expensive solution as salaries for nurse anaesthetists, which average £50 000, are more than twice those of residents. 

The US Health Care Financing Administration recently announced a proposal to eliminate the federal requirement for supervision of nurse anaesthetists by physicians. This move is being supported by the American Association of Nurse Anesthetists. If approved, the proposal could allow independent practice in some states. The American Society of Anesthesiologists has urged its members to respond “vigorously” to the proposal. 

Why can’t nurses be a part of anaesthesia in Britain? The simple answer is: “It’s too late.” Assuming that a pool of sufficiently trained and motivated nurses who are willing to take up the challenge actually exists, will there be any jobs for them by the time they emerge from training? Who should train and accredit nurse anaesthetists—and could recruitment to nurse anaesthesia deprive other areas of its skilled practitioners? Unlike his or her American counterpart, the average British trainee in anaesthesia often works with little or no supervision. British trainees are paid less than their regular rates of pay for contractual overtime. We believe that it is unlikely that nurses would tolerate being used to replace trainees in anaesthesia under the same conditions. Employing nurses as replacements for consultants, which could conceivably happen in the United States, would threaten the fundamental involvement of the practice of medicine in anaesthesia. 

The practice of anaesthesia is much more than the administration of anaesthetics and for this reason anaesthesia should remain, at least in the United Kingdom, a physician based service.
Transtracheal Anesthesia for Bronchoscopy
Authors: Dwight E. Harken, Arnold M. Salzberg
Journal: New England Journal of Medicine (1948)

BRONCHOSCOPY contributes greatly to the diagnosis and treatment of intrathoracic disease. It is at once apparent that proper anesthesia serves the interest of both the bronchoscopist and the patient.In a search for the most satisfactory anesthetic technic, the various methods of administering topical agents have been explored, the gamut of general anesthetics has been run, and a series of bronchoscopic and esophagoscopic examinations have been conducted under bilateral vagus-nerve block. The technic described below appears to us to serve best the patient and bronchoscopist. The safety of this method is adequately established by experience with more than 1000 patients . . .
<i>Escherichia coli</i>Endocarditis after Repair of Ventricular Septal Defects
Authors: Robert E. Stanton, George G. Lindesmith, Bert W. Meyer
Journal: New England Journal of Medicine (1968)

Therapy of two children with ventricular septal defects who were successfully treated for postcardiotomy Escherichia coli endocarditis included ampicillin, kanamycin and reoperation, with removal of the patch in one child and removal of infected sutures in the other. An additional complication was an aneurysm of the right ventricle that was secondary to the infection and that required resection. This child had two additional ventriculotomies in addition to the original corrective surgery during the six and a half months in the hospital. This child also had a Candida albicans bloodstream infection that was successfully eradicated with amphotericin B. A review of the pertinent literature indicates that although the incidence of postcardiotomy endocarditis is relatively low at 0.1 to 2.7 per cent, the mortality varies from 40 to 100 per cent. A combined approach to therapy with appropriate antibiotics in resistant postcardiotomy endocarditis, followed by reoperation, with removal of foreign material, may provide the best results.
Resection of colorectal cancer (CRC) metastases after bevacizumab (BV) treatment for first-line therapy: Results of the ETNA cohort study.
Authors: E. Terrebonne, D. Smith, Y. Becouarn, P. Michel, R. Guimbaud, D. Auby, A. sa Cunha, A. Ravaud, M. Rouyer, A. Fourrier-Réglat
Journal: Journal of Clinical Oncology (2010)

3594 Background: BV associated with chemotherapy has been demonstrated to improve overall survival (OS) in metastatic CRC (mCRC). This allows to consider secondary resection of metastases for the initially unresectable mCRC. Methods: ETNA is a cohort study conducted in 28 French centers. It included patients (pts) initiating BV from Jan 2006 to Dec 2007. Those treated in first-line therapy for mCRC were followed for 24 months. Effectiveness for pats with secondary resection of metastases and curative intent is presented here. Results: A total of 411 pts had first-line therapy with BV for mCRC: 347 were analyzable after 24 months of follow-up, and 67 (19.3%) had metastasis resection (pts operated, oPts). oPts main baseline characteristics were: mean age: 61.6 y, male: 46.3%, ECOG 0-1: 91.0% and one metastatic site: 58.2%; those of not operated pts (noPts) were: mean age: 64.0 y, male: 60.0%, ECOG 0-1: 77.5% and one metastatic site: 55.7%. Among the oPts, resection site was: liver n = 44, lung n = 10, other n = 20. Results of surgery available for 56 oPts were: R0-R1: 85.7%, R2: 14.3%. The median time from BV initiation to first resection was 207 days. For oPts, BV was mainly associated with irinotecan-based regimens (97.0%) and with FOLFOX regimens (3.0%); for noPts it was: FOLFIRI: 83.6%, XELIRI: 2.9%, FOLFOX: 10.7%, XELOX: 2.5% and FOLFIRINOX: 0.4%. Objective response rate was 85.1% including 32.8% complete response (vs. 49.3% and 5.4% for noPts), stable disease 14.9% (vs. 30.0%) and absence of progressive disease (vs. 17.1%). Median duration of BV treatment was 6.9 months and of first-line therapy was 14.3 months (vs. 5.0 and 8.3 months for noPts). Median PFS was 13.6 months for oPts, the 1-yr OS rate was 94.0% (95%CI 84.9-97.7) and the 2-yr OS rate was 81.7% (95%CI 70.0-89.2) (vs. for noPts: median PFS 9.0 months, 1-yr OS rate 75.2% [95%CI 69.6-79.8] and the 2-yr OS rate 44.5% [95%CI 38.5-50.4]). Median OS was not reached for oPts and was 21.9 months for noPts. Conclusions: For pts treated by BV in a real-life setting, secondary resection of mCRC for initially unresectable metastases was possible for 19% of pts with 85.7% R0-R1. Evaluation of morbidity and longer follow-up will allow the real long-term benefit to be studied. No significant financial relationships to disclose.
55O_PR Phase III HannaH study of subcutaneous or intravenous trastuzumab for HER2-positive early breast cancer: Exploratory subgroup analyses of pathological complete response and 3-year event-free survival by body weight and anti-drug antibody status
Authors: J.-S. Ahn, C. Jackisch, R. Hegg, D. Stroyakovskiy, B. Melichar, S.-C. Chen, A. Crepelle-Flechais, S. Lauer, M. Shing, X. Pivot
Journal: Annals of Oncology (2015)
Free Small and IgG-Associated Large Hepatitis B e antigen in the Serum and Glomerular Capillary Walls of Two Patients with Membranous Glomerulonephritis
Authors: Yasuo Takekoshi, Masato Tanaka, Yuzo Miyakawa, Hiroshi Yoshizawa, Kazuaki Takahashi, Makoto Mayumi
Journal: New England Journal of Medicine (1979)

Nephrotic syndrome developed in two children who carried hepatitis B virus. Both their serums contained hepatitis B surface antigen and hepatitis B e antigen (HBeAg). Two physicochemically and immunologically different categories of HBeAg activity were identified in their serums — i.e., small molecular (free) and large molecular (associated with IgG). Their kidney-biopsy specimens disclosed pathologic changes typical of membranous glomerulonephritis. By a fluorescent-antibody technic, HBeAg was found to be deposited in diffuse granular fashion, along glomerular capillary walls, together with IgG and β1C, but no deposition of hepatitis B surface antigen was detected. The presence of HBeAg in association with IgG both in the serum and in the kidneys of these patients suggests that HBeAg caused membranous glomerulonephritis by inducing the formation and deposition of immune complexes. (N Engl J Med 300:814–819, 1979)
Subjects' rights, freedom of inquiry, and the future of research in the addictions
Authors: R E Meyer
Journal: American Journal of Psychiatry (1977)

Since the recent passage of regulations concerning subjects' rights and freedom on inquiry, opposition by the public and others to some areas of research in the addictions has prevented its implementation or continuation. Research investigators in the biomedical and behavioral sciences have been placed in the position of defending their work in an adversary climate. The author points out the importance of transmitting to the public, the scientific community, and legislators the investigators' concern that "subjects' rights" not be viewed only in a legalistic context, but also in the context of not harming the patient.
From a Physician in Lower Manhattan
Authors: Mark E. Horowitz
Journal: New England Journal of Medicine (2001)

To the Editor: I have a private practice, with two other family physicians, in an office in the financial district of lower Manhattan, five blocks (300 m) from the site of the World Trade Center. Most of our patients work or live in lower Manhattan, including many who worked in the World Trade Center or its vicinity. We have learned of the deaths of at least four of our patients who were trapped in the collapse of the World Trade Center towers on September 11. At the time of the attacks, our office had just opened for the day. (I . . .
Diethylnitrosamine-Induced Hepatic Degeneration and Neoplasia in the Aquarium Fish, Brachydanio rerio
Authors: Mearl F. Stanton
Journal: JNCI Journal of the National Cancer Institute (1965)

Journal Article Diethylnitrosamine-Induced Hepatic Degeneration and Neoplasia in the Aquarium Fish, Brachydanio rerio Get access Mearl F. Stanton Mearl F. Stanton Laboratory of Pathology, National Cancer Institute,3Bethesda, Maryland 2I wish to express my appreciation to Mr. Gebhard Gsell for the photomicrographs and to Mr. Joseph M. Albrecht and staff for histologic preparations. Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 34, Issue 1, January 1965, Pages 117–130, https://doi.org/10.1093/jnci/34.1.117 Published: 01 January 1965 Article history Received: 29 June 1964 Published: 01 January 1965
Rosette-Forming Cells, Immunologic Deficiency Diseases and Transfer Factor
Authors: Joseph Wybran, Alan S. Levin, Lynn E. Spitler, H. Hugh Fudenberg
Journal: New England Journal of Medicine (1973)

Lymphocytes from peripheral blood of normal subjects and of patients with various immunologic deficiency diseases were studied to determine the percentage able to bind with sheep erythrocytes in a formation called a rosette. These rosette-forming cells represent thymus-derived cells. Patients with Nezelof syndrome, Wiskott-Aldrich syndrome, and chronic mucocutaneous candidiasis, all diseases with defects in cellular immunity, had low percentages of these cells. Six patients with acquired hypogammaglobulinemia, a defect in humoral immunity, had normal numbers. Three patients with Wiskott-Aldrich syndrome responded clinically and immunologically to administration of transfer factor, and these patients showed significant increases in rosette-forming cells. One patient with Wiskott-Aldrich syndrome and those with chronic mucocutaneous candidiasis who did not respond to transfer factor did not show increases in rosette-forming cells.
A pilot study to compare FXR expression in normal and malignant tissue in receptor-positive early-stage breast cancer
Authors: N. Kounalakis, S. Lau, D. Darling, M. Palomares, M. Senthil, L. Lai
Journal: Journal of Clinical Oncology (2009)

e14645 Background: Farnesoid X receptor (FXR), a nuclear receptor, is a ligand dependent transcriptional factor regulating cholesterol and carbohydrate metabolism. Recently, FXR was shown to have a contributing role in colorectal cancer. We hypothesize that FXR expression changes from normal to premalignant to malignant tissue in patients with breast cancer. Methods: We identified 16 paired formaldehyde fixed, paraffin embedded tissue (normal, premalignant, and malignant) from patients with receptor positive, early stage breast cancer. Clinical information was extracted from a prospective database initiated in 2006 under institutional approval. Immunohistochemical staining of FXR using a validated polyclonal antibody was completed with appropriate positive and negative controls. The slides were graded independently by two investigators using an agreed upon scale to detect the percentage of positively stained cells to the nearest 10 th percentile. Statistical analysis was performed by ANOVA and Student's t-test. A p-value of 0.05 was considered significant in all analyses. Results: Normal tissue and invasive cancer was identified in all 16 patient specimens. Of the 16 invasive cancers, 12 were ductal and 4 were lobular. 8/16 (50%) of the specimens also contained non-invasive cancer. 5/16 patients (31%) had N1 disease. FXR expression did not correlate with grade, histology, stage, or lymph node status. However, FXR expression increases with malignant transformation of the breast cancer cell. The mean percentage of cells staining positive for FXR in normal breast tissue was 58%, non-invasive 72% and invasive 79%. FXR staining in normal breast tissue was significantly less when compared to both invasive and noninvasive cancer (p&lt; 0.007). Conclusions: FXR expression is upregulated in breast cancer when compared with expression in normal tissue and appears to progressively increase along the continuum of malignancy. Our pilot study results warrant further evaluation into FXR as a predictive biomarker for breast cancer, given the ability to target FXR via development of non-toxic oral ligands. No significant financial relationships to disclose.
Combinatorial targeting of nuclear export and translation of RNA inhibits aggressive B-cell lymphomas
Authors: Biljana Culjkovic-Kraljacic, Tharu M. Fernando, Rossella Marullo, Nieves Calvo-Vidal, Akanksha Verma, ShaoNing Yang, Fabrizio Tabbò, Marcello Gaudiano, Hiba Zahreddine, Rebecca L. Goldstein, Jayeshkumar Patel, Tony Taldone, Gabriela Chiosis, Marco Ladetto, Paola Ghione, Rodolfo Machiorlatti, Olivier Elemento, Giorgio Inghirami, Ari Melnick, Katherine L. B. Borden, Leandro Cerchietti
Journal: Blood (2015)