tbuckley/cabot-search huggingface dataset:
Improved nonclinical pharmacokinetics and biodistribution of a new PPAR pan-agonist and COX inhibitor in nanocapsule formulation
Authors: Giani Martins Garcia, Líliam Teixeira Oliveira, Ivan da Rocha Pitta, Maria do Carmo Alves de Lima, José Mário Carneiro Vilela, Margareth Spangler Andrade, Dulcinéia Saes Parra Abdalla, Vanessa Carla Furtado Mosqueira
Journal: Journal of Controlled Release (2015)
OPAT outcomes in endocarditis
Authors: C. J. A. Duncan, D. A. Barr, R. A. Seaton
Journal: BMJ (2013)

As Chapman states,1 outpatient parenteral antibiotic therapy (OPAT) is increasingly seen as a viable management option for high risk patients with infective endocarditis. But in most studies treatment success is judged on clinical grounds (such as cure of infection). Because the benefits of this treatment derive from avoiding hospital admission while providing high standards of care to “low risk” patients, judgment on the …
Book Review Cities and the Health of the Public Edited by Nicholas Freudenberg, Sandro Galea, and David Vlahov. 364 pp. Nashville, Vanderbilt University Press, 2006. $79.95 (cloth); $34.95 (paper). 978-0-8265-1511-7 (cloth); 978-0-8265-1512-4 (paper).
Authors: Amasa B. Ford
Journal: New England Journal of Medicine (2007)
The path of non-conformity
Authors: K. Abbasi
Journal: BMJ (2014)

What is courage? Is courage possible without fear? Nelson Mandela believed that courage was not the absence of fear but the triumph over it: “The brave man is not he who does not feel afraid, but he who conquers that fear.” Each news report brings us stories of courage, from the inhumanity of Europe’s battle trenches of a century ago to the humanitarian and public health crisis in Gaza today, and yet no statesman of Mandela’s calibre is able to guide us to a less fearful place.

Courage is also treating patients with Ebola disease, writes Margaret McCartney, who sympathises with the fear that health workers might feel and admires those who continue to risk their lives to save patients ( BMJ 2014;349:g4987, doi:10.1136/bmj.g4987). “I am afraid for my life,” said …
The role of interventional radiology in trauma
Authors: I. A Zealley, S. Chakraverty
Journal: BMJ (2010)

#### Summary points

Most preventable deaths from trauma are caused by unrecognised and therefore untreated haemorrhage, particularly in the abdomen. Haemorrhage causes early deaths, and the associated hypovolaemic shock leads to secondary brain injury and contributes to late death from multiorgan failure.1 Early management is focused on resuscitation and the diagnosis and treatment of life threatening bleeding to prevent the lethal metabolic disturbance triad of acidosis, hypothermia, and coagulopathy.2

Many aspects of immediate trauma care suffer from a lack of high quality prospective research. This review is based predominantly on evidence from retrospective cohort series and is subject to the limitations inherent in this type of level 2 research.3 There are no prospective randomised controlled trials of interventional radiology in major trauma. Although the volume of level 2 evidence is substantial and contains few contradictory findings, no robust level 1 evidence yet exists. This review aims to summarise the evidence supporting the use of interventional radiological techniques in the management of haemorrhage caused by blunt abdominal trauma.

Interventional radiology uses minimally invasive endovascular techniques to stem haemorrhage. Endovascular haemostasic techniques are established in non-trauma clinical scenarios. In trauma, the main application is to control endovascular haemorrhage by blocking bleeding vessels (transcatheter arterial embolisation (fig 1⇓) or relining …
A trans-lentiviral packaging cell line for high-titer conditional self-inactivating HIV-1 vectors
Authors: Adam S. Cockrell, Hong Ma, Kailing Fu, Thomas J. McCown, Tal Kafri
Journal: Molecular Therapy (2006)

Lentiviral vector safety has been the impetus underlying the progress in packaging cell line development. The prospects of generating replication-competent lentiviruses (RCLs) and the potential for vector mobilization continue to be the driving force for the advancement of packaging cell lines. We have exploited the trans-lentiviral packaging system to develop the SODk3 packaging cell line for the generation of conditional self-inactivating (cSIN) vectors. Separating the gag-pol genome into two distinct expression cassettes (gag-pro and vpr-RT-IN) may reduce the potential for RCL formation, while concurrently employing cSIN vectors supports retention of the SIN phenotype in target cells and alleviates technical constraints associated with generating producer cell lines. Through development of the SODk3 packaging cell line we determined that the ratio of Gag/Pol in vector particles may be used as an indicator for packaging cell clones that yield high vector titers. Conditional SIN vector titers (1 x 10(7) TU/ml) were augmented through clonal selection. Distinct producer cell clones revealed a parallel between vector titer and transgene expression levels. We exploited this observation to demonstrate that incorporation of an internal ribosome entry site between the GFP marker and a relevant transgene affords efficient selection of high-titer producer cell lines. Furthermore, cSIN vectors generated from SODk3 packaging cells imparted efficient transduction of primary human fibroblasts, an indication of the future applicability of the SODk3 packaging cell line.
Clinical Research&lt;SUBTITLE&gt;Perceptions, Reality, and Proposed Solutions&lt;/SUBTITLE&gt;
Authors: David G. Nathan
Journal: JAMA (1998)

Context.—The proportion of investigators applying for clinical research grants from the National Institutes of Health (NIH) who are physicians has declined from 40% 30 years ago to 25% today.Objective.—To recommend NIH policy changes that might encourage physician investigators to undertake careers in clinical research, eg, patient-oriented research, epidemiologic and behavioral studies, outcomes research, and health services research.Participants.—The NIH Director's Panel on Clinical Research comprised 14 physicians from academia and industry, chosen by the director. They met in numerous closed sessions and in 5 public meetings from July 1995 to November 1997.Consensus Process.—In addition to expert opinion and pertinent literature, data sources included the training characteristics of applicants to NIH who were funded or not. Topics considered included financing of clinical research, recruitment, training, and retention of future clinical investigators, conduct of clinical trials, and peer review of clinical research. Consensus was reached and recommendations were made in response to an interim report, widely circulated to the biomedical community, written by members of the panel, which contained preliminary recommendations.Conclusions.—The panel's final recommendations to NIH included maintaining at least the present proportion of NIH funding for clinical research; continuing mentored opportunities in clinical research for medical students; promoting clinical research training by offering didactic courses and grant opportunities in clinical research to nascent investigators emerging from specialty training programs and providing partial salary support for mentors; restructuring study sections that review patient-oriented research applications to include more physicians; encouraging clinical investigators and basic scientists to work closely together and weld collaborations between academic clinical investigators and colleagues in pharmaceutical and biotechnology companies; and developing a joint policy between academic health centers and NIH for the support of clinical research and clinical research training.
B-cell depletion with anti-CD20 ameliorates autoimmune cholangitis but exacerbates colitis in transforming growth factor-β receptor II dominant negative mice
Authors: Yuki Moritoki, Zhe-Xiong Lian, Keith Lindor, Joseph Tuscano, Koichi Tsuneyama, Weici Zhang, Yoshiyuki Ueno, Robert Dunn, Marilyn Kehry, Ross L. Coppel, Ian R. Mackay, M. Eric Gershwin
Journal: Hepatology (2009)

The treatment of primary biliary cirrhosis (PBC) with conventional immunosuppressive drugs has been relatively disappointing and there have been few efforts in defining a role for the newer biological agents useful in rheumatoid arthritis and other systemic autoimmune diseases. In this study we took advantage of transforming growth factor-β (TGF-β) receptor II dominant negative (dnTGF-βRII) mice, a mouse model of autoimmune cholangitis, to address the therapeutic efficacy of B-cell depletion using anti-CD20. Mice were treated at either 4-6 weeks of age or beginning at 20-22 weeks of age with intraperitoneal injections of anti-CD20 every 2 weeks. We quantitated B-cell levels in all mice as well as antimitochondrial antibodies (AMA), serum and hepatic levels of proinflammatory cytokines, and histopathology of liver and colon. In mice whose treatment was initiated at 4-6 weeks of age, anti-CD20 therapy demonstrated a significantly lower incidence of liver inflammation associated with reduced numbers of activated hepatic CD8+ T cells. However, colon inflammation was exacerbated. In contrast, in mice treated at 20-22 weeks of age, anti-CD20 therapy had relatively little effect on either liver or colon disease. As expected, all treated animals had reduced levels of B cells, absence of AMA, and increased levels in sera of tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), and chemokine (C-C motif) ligand (CCL2) (monocyte chemoattractant protein 1 [MCP-1]). Conclusion: These data suggest potential usage of anti-CD20 in early PBC resistant to other modalities, but raise a cautionary note regarding the use of anti-CD20 in inflammatory bowel disease. (HEPATOLOGY 2009.)
ON THE MECHANISM OF IMMUNITY IN TUBERCULOSIS
Authors: Max B. Lurie
Journal: The Journal of Experimental Medicine (1936)

1. There is an extracellular factor which inhibits the growth of tubercle bacilli in immunized rabbits. 2. Extracellular factors localize carbon particles, trypan blue and tubercle bacilli at the site of introduction to a greater extent in the immunized than in the normal animal. 3. This greater fixation is brought about by an increase in the density and extent of the fibrin barrier formed about the focus of the immunized animal. The more pronounced in vivo agglutination of tubercle bacilli and carbon particles in the vaccinated or tuberculous rabbit also tends to immobilize them in the tissues. 4. The growth inhibitory and localizing agents are effective in the fixation of small doses on reinfection at the portal of entry. 5. With large doses on reinfection, the increased lymph flow resulting from the intensified inflammation in the immunized animal brings about a more rapid dissemination of the bacilli to the draining lymph nodes than in the normal animal. 6. The most significant factor in immunity is the increased capacity of the rapidly mobilized mononuclear phagocytes to destroy tubercle bacilli. The impotent polymorphonuclear leukocytes quickly disappear from the site of reinfection. 7. The invading bacilli that reach the draining lymph nodes of the immunized animal are retarded in multiplication or destroyed by these phagocytes. 8. Vaccination of rabbits with BCG brings into play the factors tending to immobilize the bacilli of reinfection, inhibit their growth and destroy them with a resulting significant immunity. 9. A virulent primary infection affords a greater immunity than one of low virulence and the host reactions are expressed by a quantitative increase in those immunity factors which operate in a vaccinated animal.
Germline Mutations Affecting Gα<sub>11</sub> in Hypoparathyroidism
Authors: Michael Mannstadt, Mark Harris, Bert Bravenboer, Sridhar Chitturi, Koen M.A. Dreijerink, David G. Lambright, Elaine T. Lim, Mark J. Daly, Stacey Gabriel, Harald Jüppner
Journal: New England Journal of Medicine (2013)

In a study reported here, genomewide linkage analysis and whole-exome sequencing were used to identify two different heterozygous Gα11 mutations in autosomal-dominant, isolated hypoparathyroidism.
Safety of Latex Prick Skin Testing in Allergic Patients-Reply
Authors: Gordon L. Sussman
Journal: JAMA (1992)

In Reply.  —This is not the first patient reported to have a possible anaphylactic reaction with the latex prick skin test.1Any potent allergen skin test in exquisitely sensitive patients has this risk. The latex testing extract is properly labeled as  cause anaphylaxis.  However, if properly done, the latex prick skin test is very safe. We have safely skin tested 115 patients,2,320 of whom had severe latex allergy. Our experience agrees with that of others.4The skin test needs to be carefully watched and immediately wiped clean with isopropyl alcohol after a positive result. This may be as soon as 5 to 7 minutes after the test.  I question whether the patient reported by Bonnekoh and Merk had an anaphylactic event. There was minimal local reaction at the test site and, in patients with anaphylaxis, we generally see a large local wheal and flare. The
Regional myocardial blood flow during cardiac tamponade in hearts with chronic coronary artery occlusion
Authors: N. WATANABE, S. YONEKURA, H F. DOWNEY
Journal: Cardiovascular Research (1987)

The effects of increased pericardial pressure on blood flow to collateral dependent and normal myocardium were investigated and the mechanisms responsible for these effects evaluated in 10 anaesthetised dogs after collateral inducement by gradual occlusion of a coronary artery. Regional myocardial blood flows were measured with radioactive microspheres during control conditions, mild tamponade, severe tamponade, and severe tamponade with aortic blood pressure held at the control value by blood volume expansion. Mild tamponade increased heart rate by 10% and decreased aortic blood pressure by 15%. Left atrial and central venous blood pressures were moderately increased, and indices of cardiac function were reduced. Blood flow to collateral dependent and normally perfused myocardium was not significantly altered, but the endocardial to epicardial flow ratio was significantly decreased in collateral dependent myocardium. Severe tamponade decreased aortic blood pressure by 45% and cardiac index by 62%. Left atrial and central venous blood pressures were appreciably increased and cardiac function indices considerably depressed. Blood flow to collateral dependent and normally perfused myocardium was decreased similarly (by 54-57%), but the endocardial to epicardial flow ratio was decreased by a greater degree in collateral dependent myocardium. During severe tamponade at control aortic blood pressure, left atrial and central venous blood pressures were further increased, but blood flow to collateral dependent and normally perfused myocardium returned to within 84% of control and endocardial to epicardial flow ratios were normal. Total peripheral vascular resistance increased during severe tamponade, but coronary vascular resistance remained constant. Thus blood flow to collateral dependent and normally perfused myocardium varied according to net coronary perfusion pressure. Tamponade induced hypotension is the dominant factor in reducing regional blood flow in hearts with well developed collateral vessels.
Diverticulitis: a Follow-up of 100 Cases
Authors: D. E. Bolt, L. E. Hughes
Journal: BMJ (1966)

Practical ConsiderationsFrom available evidence lymphography must be considered to be a potentially dangerous method of investigation.However, if certain precautions are taken no serious complications should develop.Particular care should be taken over the amount of Lipiodol Ultra Fluid injected, especially after lymphadenectomy or in the presence of lymphatic obstruction, and the procedure should not be undertaken when there is pre-existing pulmonary disease.To prevent the occurrence of thrombo-embolism it is suggested that the limbs should rest on a soft mattress, and should periodically be passively exercised while the investigation is proceeding. SummaryLymphography with Lipiodol Ultra Fluid was successfully performed in 110 out of a consecutive series of 115 female patients with a carcinoma arising from the genital tract.The complications associated with the procedure were recorded.In 98 the study was bilateral and in 12 unilateral.The investigation was repeated in 20 patients ; in eight this was bilateral and in 12 unilateral.The total amount of contrast medium injected in any patient did not exceed 16 ml.Minor complications, which have been described by most other workers, developed in 30% of cases, but there has been little previous reference to two complications which occurred thrombo-embolism and haemoptysis.The occurrence of thrombo-embolism in three patients may have been precipitated by venous stasis resulting from complete immobility of the limbs over a period of three to four hours.Haemoptysis which occurred in six patients probably resulted from breakdown of oil and release of fatty acids in the lungs.The repeat studies indicated that no permanent interference with the internodal or intranodal lymph circulation develops after lymphography.
Wrong Medicine: Doctors, Patients, and Futile Treatment
Authors: Bernard H. Adelson
Journal: JAMA (1996)

The impetus for this book, according to its authors, was "the desire to restore a vision of medicine's proper ends and [to] reform medical practice." The book does not completely attain these lofty ideals, but it does present to its readers (members of the medical profession and the lay public) a well-reasoned analysis of the concept of futility in medical practice. The book comprises 10 short chapters which, in logical sequence, discuss and define the meaning and the ethical implications of medical futility. The chapter titles give the flavor of the book: "Are Doctors Supposed to be Doing This?" "Why It Is Hard To Say No," "Why We Must Say No," "Families Who Want Everything Done," "Futility and Rationing," "Medical Futility in a Litigious Society," "Ethical Implications of Medical Futility," "The Way It Is Now/ The Way It Ought To Be: For Patients," "The Way it is Now/The Way It
Phosphorylation of Glycogen Synthase Kinase-3β During Preconditioning Through a Phosphatidylinositol-3-Kinase–Dependent Pathway Is Cardioprotective
Authors: Haiyan Tong, Kenichi Imahashi, Charles Steenbergen, Elizabeth Murphy
Journal: Circulation Research (2002)

We previously reported that activation of phosphatidylinositol-3-kinase (PI3-kinase) is involved in ischemic preconditioning (PC). Our goal was to determine downstream targets of PI3-kinase. In perfused rat hearts, PC (4 cycles of 5 minutes of ischemia and 5 minutes of reflow) increased phosphorylation of glycogen synthase kinase-3beta (GSK-3beta), a downstream target of PI3-kinase and protein kinase B (PKB), an effect that was blocked by wortmannin. Because phosphorylation inactivates GSK-3beta, we examined whether PC-induced phosphorylation and inhibition of GSK-3beta is important in PC by using two inhibitors of GSK-3beta, lithium and SB 216763. Pretreatment of perfused rat hearts with lithium or SB 216763, before ischemia, mimicked the protective effects of PC; hearts treated with either lithium or SB 216763 had improved postischemic function and reduced infarct size. These findings indicate that inhibition of GSK-3beta is protective and that this PI3-kinase--dependent signaling pathway may play an important role in ischemic preconditioning.
Role of the TGF-β/Alk5 Signaling Pathway in Monocrotaline-induced Pulmonary Hypertension
Authors: Ari L. Zaiman, Megan Podowski, Satya Medicherla, Kimberley Gordy, Fang Xu, Lijie Zhen, Larissa A. Shimoda, Enid Neptune, Linda Higgins, Alison Murphy, Sarvajit Chakravarty, Andrew Protter, Pravin B. Sehgal, Hunter C. Champion, Rubin M. Tuder
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Pulmonary arterial hypertension is a progressive disease characterized by an elevation in the mean pulmonary artery pressure leading to right heart failure and a significant risk of death. Alterations in two transforming growth factor (TGF) signaling pathways, bone morphogenetic protein receptor II and the TGF-β receptor I, Alk1, have been implicated in the pathogenesis of pulmonary hypertension (PH). However, the role of TGF-β family signaling in PH and pulmonary vascular remodeling remains unclear.Objectives: To determine whether inhibition of TGF-β signaling will attenuate and reverse monocrotaline-induced PH (MCT-PH).Methods: We have used an orally active small-molecule TGF-β receptor I inhibitor, SD-208, to determine the functional role of this pathway in MCT-PH.Measurements and Main Results: The development of MCT-PH was associated with increased vascular cell apoptosis, which paralleled TGF-β signaling as documented by psmad2 expression. Inhibition of TGF-β signaling with SD-208 significantly attenuated the development of the PH and reduced pulmonary vascular remodeling. These effects were associated with decreased early vascular cell apoptosis, adventitial cell proliferation, and matrix metalloproteinase expression. Inhibition of TGF-β signaling with SD-208 in established MCT-PH resulted in a small but significant improvement in hemodynamic parameters and medial remodeling.Conclusions: These findings provide evidence that increased TGF-β signaling participates in the pathogenesis of experimental severe PH.
Response modification in carcinogenesis.
Authors: P A Cerutti
Journal: Environmental Health Perspectives (1989)

A major goal in multistep carcinogenesis research is the integration of recent findings obtained by sophisticated molecular-genetic and cytogenetic analysis of cancer into the more descriptive concepts of experimental pathology. It is proposed that the creation of a promotable cell in carcinogenic initiation requires a response modification to extracellular or intercellular signals. Different types of response modification can be distinguished: changes in the receptors for growth and differentiation factors and their cytoplasmic and nuclear signal transduction pathways; increased resistance of initiated cells to cytotoxic agents; alterations in junctional cell-to-cell communications. The challenge of a response-modified cell to an appropriate promoter results in its selection and clonal expansion, usually to a benign tumor. In addition, for malignancy, chromosomal changes are required that affect cellular functions that can play a role early or late in tumorigenesis. These concepts are illustrated with examples from oncogene research and oxidant promotion.
Specialized tissues of the heart; proceedings of symposium on specialized tissues of the heart, August 1960, Rio de Janeiro
Authors: S. E. Gould
Journal: JAMA (1963)

The monograph contains 13 papers dealing with the histology, micromorphology, and physiology of the conducting tissue of the heart. Only a few of the interesting items presented will be mentioned. Robb and Petri reconstructed hearts of embryo monkeys and demonstrated two definite but diffuse pathways between the sino-atrial (SA) and atrioventricular (AV) nodes. Their observations check with the electrical findings of Paes de Carvalho in independent studies on the rabbit's heart. Treux measured the heart rate and diameters of myocardial and Purkinje fibers in 13 species of birds and mammals. He found that the diameter of the ventricular fibers varies only from 6.8μ in the dog to 15.0μ in the whale ( cardiac weight, 350 lb ) and in cattle. In all species examined, the diameter of the atrial cardiac fibers exceeded that of the ventricular cardiac fibers, and the diameter of the subendocardial Purkinje fibers was much greater than that of