tbuckley/cabot-search huggingface dataset:
Hypoxia/reoxygenation causes inflammatory response in transgenic sickle mice but not in normal mice
Authors: D.K. Kaul, R.P. Hebbel
Journal: Journal of Clinical Investigation (2000)

In sickle cell anemia, the initiation, progression, and resolution of a vasoocclusive episode may present features of ischemia-reperfusion injury, with recurrent episodes of ischemia/hypoxia and reoxygenation promoting inflammation. Here, we have tested the hypothesis that hypoxia/reoxygenation triggers inflammation in the transgenic sickle mouse. In these mice, even at ambient air, peripheral leukocyte counts are elevated by 1.7-fold and neutrophil counts by almost 3-fold. Two hours of hypoxia, followed by reoxygenation, induced a greater than normal rolling flux and adhesion of leukocytes in these mice, but no leukocyte extravasation. When 3 hours of hypoxia was followed by reoxygenation, sickle mice, but not normal mice, showed a distinct inflammatory response characterized by an increased number of adherent and emigrated leukocytes. Because these events, which are exaggerated in sickle mice, are not seen in response to hypoxia alone, we conclude that they represent a form of reperfusion injury. Studies using an H2O2-sensitive probe revealed clear evidence of oxidant production in vascular endothelial cells after hypoxia/reoxygenation in sickle mice. Infusion of an anti–P-selectin antibody, but not an anti–E-selectin antibody, completely inhibited this inflammatory response and significantly increased wall shear rates. These findings suggest that leukocyte-endothelium interaction contribute to vasoocclusive events in the sickle mice and perhaps in human sickle disease.
Abstract IA05: Fanconi's anemia: Emerging therapeutic opportunities
Authors: Markus Grompe, John Postlethwait, Alan D'Andrea, Susan Olson, Qingshuo Zhang, Grover Bagby
Journal: Cancer Research (2014)

Abstract Fanconi's anemia (FA) is a genetically heterogeneous inherited disorder characterized by bone marrow failure, birth defects and cancer susceptibility. At the cellular level, FA features hypersensitivity to DNA cross-linking agents, cell cycle abnormalities and abnormal responses to cytokines. Therapy for the hematopoietic defects of FA has consisted of supportive care, stem cell transplantation and administration of androgens such as oxymetholone. Unfortunately, even successfully transplanted FA patients have a very high risk for subsequent solid tumors, especially squamous cell carcinomas of oropharyngeal and urogenital areas. The pharmacological treatment of FA has been unchanged for several decades and for this reason our group has embarked on systematic search for small molecule therapeutics that could benefit FA patients. This effort has been made possible by the cloning of 16 FA genes and biochemical insights into the function of FA proteins. Mouse models, zebra fish models and FA patient cell lines, including IPSC are available for screening and validation. The specific goals of small molecule interventions are to delay or prevent hematopoietic failure and also to delay or prevent carcinogenesis. To date we have shown that the superoxide dismutase mimetic drug Tempol can significantly delay tumor formation in FA mice. Similarly, resveratrol clearly improved hematopoiesis in the same model. Medium throughput screens have revealed numerous new molecules which ameliorate the FA phenotypes of cells, mice and zebrafish respectively. Using genetic approaches we also have identified the p53 pathway as a therapeutic target in FA. These therapeutic opportunities and progress in FA small molecule screening will be discussed. Citation Format: Markus Grompe, John Postlethwait, Alan D'Andrea, Susan Olson, Qingshuo Zhang, Grover Bagby. Fanconi's anemia: Emerging therapeutic opportunities. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Susceptibility and Cancer Susceptibility Syndromes; Jan 29-Feb 1, 2014; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(23 Suppl):Abstract nr IA05. doi:10.1158/1538-7445.CANSUSC14-IA05
Clonal Evolution of Resistance to Imatinib in Patients with Metastatic Gastrointestinal Stromal Tumors
Authors: Jayesh Desai, Sridhar Shankar, Michael C. Heinrich, Jonathan A. Fletcher, Christopher D. Fletcher, Judi Manola, Jeffrey A. Morgan, Christopher L. Corless, Suzanne George, Kemal Tuncali, Stuart G. Silverman, Annick D. Van den Abbeele, Eric van Sonnenberg, George D. Demetri
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Resistance to imatinib mesylate is emerging as a clinical challenge in patients with metastatic gastrointestinal stromal tumors (GIST). Novel patterns of progression have been noted in a number of these patients. The objective of this study was to correlate molecular and radiologic patterns of imitinib-refractory disease with existing conventional criteria for disease progression. Experimental Design: Patients with metastatic GIST treated with imatinib were followed with serial computed tomography/magnetic resonance imaging and [18F]fluoro-2-deoxy-d-glucose positron emission tomography. Where feasible, biopsies were done to document disease progression. Results: A total of 89 patients were followed for a median of 43 months. Forty-eight patients developed progressive disease. A unique “resistant clonal nodule” pattern (defined as a new enhancing nodular focus enclosed within a preexisting tumor mass) was seen in 23 of 48 patients and was thought to represent emergence of clones resistant to imatinib. Nodules were demonstrable a median of 5 months (range, 0-13 months) before objective progression defined by tumor size criteria and were the first sign of progression in 18 of 23 patients. Median survival among patients whose first progression was nodular was 35.1 months, compared with 44.6 months for patients whose first progression met Southwest Oncology Group criteria (P = 0.31). Comparative tumor biopsies were done in 10 patients at baseline and from progressing nodules. Genotypic analyses of KIT and PDGFRA kinases were done, revealing new activating kinase mutations in 80% (8 of 10) of these patients. Conclusion: The resistant clonal nodule is a unique pattern of disease progression seen in patients with GISTs after an initial response to imatinib and reflects the emergence of imatinib-resistant clones. Conventional tumor measurements (Southwest Oncology Group/Response Evaluation Criteria in Solid Tumors) do not detect this subtle finding. A new enhancing nodule growing within a preexisting tumor mass should be classified as a new lesion and be regarded, at least, as partial progression of GIST.
Design and validation of a histological scoring system for nonalcoholic fatty liver disease†
Authors: David E. Kleiner, Elizabeth M. Brunt, Mark Van Natta, Cynthia Behling, Melissa J. Contos, Oscar W. Cummings, Linda D. Ferrell, Yao‐Chang Liu, Michael S. Torbenson, Aynur Unalp‐Arida, Matthew Yeh, Arthur J. McCullough, Arun J. Sanyal
Journal: Hepatology (2005)

Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis in the absence of a history of significant alcohol use or other known liver disease. Nonalcoholic steatohepatitis (NASH) is the progressive form of NAFLD. The Pathology Committee of the NASH Clinical Research Network designed and validated a histological feature scoring system that addresses the full spectrum of lesions of NAFLD and proposed a NAFLD activity score (NAS) for use in clinical trials. The scoring system comprised 14 histological features, 4 of which were evaluated semi-quantitatively: steatosis (0-3), lobular inflammation (0-2), hepatocellular ballooning (0-2), and fibrosis (0-4). Another nine features were recorded as present or absent. An anonymized study set of 50 cases (32 from adult hepatology services, 18 from pediatric hepatology services) was assembled, coded, and circulated. For the validation study, agreement on scoring and a diagnostic categorization ("NASH," "borderline," or "not NASH") were evaluated by using weighted kappa statistics. Inter-rater agreement on adult cases was: 0.84 for fibrosis, 0.79 for steatosis, 0.56 for injury, and 0.45 for lobular inflammation. Agreement on diagnostic category was 0.61. Using multiple logistic regression, five features were independently associated with the diagnosis of NASH in adult biopsies: steatosis (P = .009), hepatocellular ballooning (P = .0001), lobular inflammation (P = .0001), fibrosis (P = .0001), and the absence of lipogranulomas (P = .001). The proposed NAS is the unweighted sum of steatosis, lobular inflammation, and hepatocellular ballooning scores. In conclusion, we present a strong scoring system and NAS for NAFLD and NASH with reasonable inter-rater reproducibility that should be useful for studies of both adults and children with any degree of NAFLD. NAS of > or =5 correlated with a diagnosis of NASH, and biopsies with scores of less than 3 were diagnosed as "not NASH."
The potential role of redox cycling as a mechanism for chemical teratogenesis.
Authors: M R Juchau, A G Fantel, C Harris, B K Beyer
Journal: Environmental Health Perspectives (1986)

A survey of the literature indicates that several chemicals whose reduced metabolites are capable of undergoing redox cycling in biological systems also possess significant teratogenic properties when tested in vivo. We have initiated investigations to determine whether the embryotoxic effects of such chemicals could result from their redox cycling properties and whether redox cycling could be an important mechanism in chemical teratogenesis. In order to obviate the potentially confounding influences of maternal factors, our initial studies have been performed with a whole embryo culture system with redox cycling agents added directly to the culture medium. Several representative redox cycling agents including doxorubicin, paraquat, a series of nitroheterocycles, nitrosofluorene, and diethylstilbestrol (converted metabolically to redox cycling quinone/semiquinone radicals) have been investigated thus far. The nitroheterocycles which bear nitro groups with comparatively high redox potentials produced a striking, asymmetric defect involving primarily the right half of the prosencephalic and mesencephalic regions. The effect was exacerbated under conditions of low O2 tension. Accumulated data to date strongly suggest that reduction of the nitro group is an essential feature in the embryotoxic mechanism. Quinones (doxorubicin, paraquat) and compounds metabolically converted to quinones (diethylstilbestrol) appeared to produce embryotoxic effects via mechanisms not associated with redox cycling. Nitrosofluorene embryotoxicity was markedly exacerbated by changes in both intra- and extracellular glutathione levels, but definitive dependence on a radical-mediated effect or redox cycling was not demonstrated.
Tamiflu: 14 flu seasons and still questions
Authors: H. M. Krumholz, C. A. Jackevicius, J. S. Ross
Journal: BMJ (2013)

At best, and bearing in mind missing data, the drug shortens flu symptoms by a day 

In the midst of a worse than average influenza season, clinicians are increasingly prescribing antiviral agents, especially oseltamivir (Tamiflu). Oseltamivir, an oral neuraminidase inhibitor, was first approved for use by the US Food and Drug Administration in 1999. It is indicated “for the treatment of acute, uncomplicated illness due to influenza infection in patients 2 weeks of age and older who have been symptomatic for no more than two days,” and, “for the prophylaxis of influenza in patients 1 year and older,” with similar indications worldwide. Despite these broad indications, some government agencies promote even wider use. For instance, the website of the US Department of Health and Human Services states that oseltamivir may prevent serious complications of flu, and the US Centers for Disease Control and Prevention’s website states that early antiviral treatment may reduce the risk of complications of flu and death.1 2 Business analysts expect rising sales of oseltamivir to reach $750m (£474m; €562m) this year alone.3

Despite such enthusiasm, some basic questions remain unanswered, including the most crucial: what do we really know about oseltamivir’s effectiveness and who benefits from treatment? With the huge number of people affected and such remarkable sales, the evidence to support the …
Heart-specific autoantibodies following murine coxsackievirus B3 myocarditis.
Authors: L J Wolfgram, K W Beisel, N R Rose
Journal: The Journal of Experimental Medicine (1985)

The sera from A.SW/SnJ mice infected with Coxsackievirus B3 (CB3) were tested on normal mouse tissue by indirect immunofluorescence. Heart-reactive antibodies were found. Absorption studies with organ extracts showed some of these autoantibodies to be heart-specific. Additional antibodies were crossreactive with skeletal muscle and kidney. These findings suggest a role for autoimmunity in the pathogenesis of murine CB3-induced myocarditis. This study establishes an animal model for the study of the humoral autoimmune response in human viral myocarditis.
Clinical Impact of Bleeding in Patients Taking Oral Anticoagulant Therapy for Venous Thromboembolism
Authors: Lori-Ann Linkins, Peter T. Choi, James D. Douketis
Journal: Annals of Internal Medicine (2003)

Background: Clinicians should consider the clinical impact of anticoagulant-related bleeding when deciding on the duration of anticoagulant therapy in patients with venous thromboembolism. Purpose: To provide reliable estimates of the clinical impact of anticoagulant-related bleeding, defined as the case-fatality rate of major bleeding and the risk for intracranial bleeding. Data Sources: MEDLINE (January 1989 to May 2003), Cochrane Controlled Trial Registry, thromboembolism experts, and reference lists; English-language literature only. Study Selection: Randomized, controlled trials and prospective cohort studies that investigated patients with venous thromboembolism who received oral anticoagulant therapy (target international normalized ratio, 2.0 to 3.0) for at least 3 months and that reported major bleeding and death as primary study outcomes. Data Extraction: Two reviewers independently extracted data on the number of anticoagulant-related major and intracranial bleeding episodes and on whether these events were fatal or nonfatal. Data Synthesis: The authors analyzed 33 studies involving 4374 patient-years of oral anticoagulant therapy. For all patients, the case-fatality rate of major bleeding was 13.4% (95% CI, 9.4% to 17.4%) and the rate of intracranial bleeding was 1.15 per 100 patient-years (CI, 1.14 to 1.16 per 100 patient-years). For patients who received anticoagulant therapy for more than 3 months, the case-fatality rate of major bleeding was 9.1% (CI, 2.5% to 21.7%), and the rate of intracranial bleeding was 0.65 per 100 patient-years (CI, 0.63 to 0.68 per 100 patient-years) after the initial 3 months of anticoagulation. Conclusion: The clinical impact of anticoagulant-related major bleeding in patients with venous thromboembolism is considerable, and clinicians should take this into account when deciding whether to continue long-term oral anticoagulant therapy in an individual patient.
Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression.
Authors: Y Sun, X Ma, D Zhou, I Vacek, A M Sun
Journal: Journal of Clinical Investigation (1996)

Porcine pancreatic islets were microencapsulated in alginate-polylysine-alginate capsules and transplanted intraperitoneally into nine spontaneously diabetic monkeys. After one, two, or three transplants of 3-7 x 10(4) islets per recipient, seven of the monkeys became insulin independent for periods ranging from 120 to 804 d with fasting blood glucose levels in the normoglycemic range. Glucose clearance rates in the transplant recipients were significantly higher than before the graft administration and the insulin secretion during glucose tolerance tests was significantly higher compared with pretransplant tests. Porcine C-peptide was detected in all transplant recipients throughout their period of normoglycemia while none was found before the graft administration. Hemoglobin A1C levels dropped significantly within 2 mo after transplantation. While ketones were detected in the urine of all recipients before the graft administration, all experimental animals became ketone free 2 wk after transplantation. Capsules recovered from two recipients 3 mo after the restoration of normoglycemia were found physically intact with enclosed islets clearly visible. The capsules were free of cellular overgrowth. Examination of internal organs of two of the animals involved in our transplantation studies for the duration of 2 yr revealed no untoward effect of the extended presence of the microcapsules.
Use of lung pressure-volume curves and helium-sulphur hexafluoride washout to detect emphysema in subjects with mild airflow obstruction
Authors: R P. Pereira, D Hunter, N B Pride
Journal: Thorax (1981)

Mild abnormalities of peripheral lung function can be detected by simple methods, but it remains difficult to determine when these changes are the result of emphysema rather than disease of the airways. We have compared the value of measurements of lung distensibility and a multibreath test of helium (He) and sulphur hexafluoride (SF<sub>6</sub>) washout in distinguishing between six men with mild impairment of airway function caused by asthma (group A) and six men with similar airway function but probable widespread emphysema (group E). In group E there were striking abnormalities in the static pressure-volume curve of the lungs (reduced lung recoil pressures, increased chord compliance, increased shape factor) and the relation between maximum expiratory flow and lung recoil pressure fell within the normal range. In group A there were only minor abnormalities in lung distensibility and maximum expiratory flow was reduced at a standard lung recoil pressure. In addition carbon monoxide transfer coefficient was reduced in group E but normal in group A. Normal values for He-SF<sub>6</sub> washout were similar to those previously described. Differences in He-SF<sub>6</sub> washout between group A and group E men were small and in part accounted for by differences in functional residual capacity. In subjects with lung disease, end-tidal He and SF<sub>6</sub> concentrations during washout were erratic and it was sometimes impossible to define a crossover point. We conclude that in our hands this technique is less useful for detecting acinar disease than are measurements of lung distensibility or carbon monoxide transfer. Considerable changes in lung distensibility may occur at an early stage in the natural history of emphysema and are readily distinguishable from the small changes that occur in mild asthma.
THE RÔLE OF HYPERSENSITIVITY IN THE PRODUCTION OF EXPERIMENTAL MENINGITIS
Authors: Caspar G. Burn, Knox H. Finley
Journal: The Journal of Experimental Medicine (1932)

1. When living or dead tubercle bacilli and their products are placed in direct contact with the leptomeninges of hypersensitive (tuberculous) animals, there is a definite clinical and pathological response. 2. The clinical response is characterized by an onset of weakness, twitchings, convulsions and death of the animal within 6 to 12 hours. 3. Histologically the central nervous system shows an extensive polymorphonuclear exudate distributed throughout the subarachnoid spaces of the brain and extending into the perivascular spaces. 4. The intensity of the response is directly proportional to the quantity of visceral tuberculosis or to the dose of tuberculin employed. 5. When small quantities of tuberculin are employed so as to permit the animal to survive longer than 24 hours, there is an exudate found in the sulci and at the base of the brain which is characterized by small lymphocytes. 6. The non-tuberculous animals when inoculated with tuberculin or tubercle bacilli revealed no clinical or pathological response. The tuberculous animals, on the other hand, when inoculated with glycerine broth always responded by a definite but slight polymorphonuclear exudate. 7. The possible relationship of the allergic state to postinfectious complications of the central nervous system is discussed.
Medical Care of the Pregnant Patient
Authors: Kathleen M. Perry
Journal: JAMA (1984)

Physicians who care for the gravidawho has or will have medical illness will welcome the multidisciplinary text<i>Medical Care of the Pregnant Patient</i>. The editors, Richard Abrams and Paul Wexler, have succeeded in gathering a laudable group of experts from the University of Colorado Medical School, Denver, to provide clear and concise chapters on the usual medical pathologies—cardiac, pulmonary, endocrine, and renal. However, the more exciting areas of the text lie in the initial chapters with their enlightening analysis of bioethical and legal aspects of high-risk care, as well as nutrition, pharmacology, and radiation effects on the maternal-fetal duo. Skillfully, Fredrich Abrams ushers us into the complex ethical arena. Abrams, who is director of the Center for Biomedical Ethics, in relatively few pages, precisely elucidates ethical definitions and philosophies. Abrams has the ability to distill a voluminous subject into an acceptable reference work for physicians of all specialties. He then
PROGNOSTIC UTILITY OF PRE-PROCEDURAL TIMI FLOW IN PATIENTS WITH NON ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROMES UNDERGOING PERCUTANEOUS CORONARY REVASCULARIZATION: THE ACUITY TRIAL
Authors: Giuseppe De Luca, Sorin Brener, Roxana Mehran, Alexandra Lansky, Ecaterina Cristea, Martin Fahy, Gregg Stone
Journal: Journal of the American College of Cardiology (2011)
Systematic Reviews: Some examples
Authors: P Knipschild
Journal: BMJ (1994)

Reviewing the literature is a scientific inquiry that needs a clear design to preclude bias.It is a real enterprise if one aims at completeness of the literature on a certain subject.Going through refereed English language journals is not enough.On line databases are helpful, but mainly as a starting point.This article gives examples of systematic reviews on vitamin C and the common cold, pyridoxine against the premenstrual syndrome, homoeopathy, and physiotherapy.You will have heard of Maastricht-in 1992 the European Union treaty was signed there.Some people dislike Maastricht because it seems to stand for the ideal of the United States of Europe, but many of us in Maastricht do not even know what the treaty is about.What we like is to sit together and enjoy our Burgun- dian way of living.Maastricht is one big sidewalk cafe.People in my town are very inventive in finding reasons for painting the town red.Of the many festivals that we have, carnival in the late winter is definitely number one.Anyone born and bred in Maastricht, would not dream of escaping the noise, the jigging, and the many beers.For almost a week we live in sin and after that we are so depleted that we need a few days off to recover.Nearly every good carnivalist gets a sore throat, a stuffy nose, and other signs of a common cold: it is a marker that we have done our duty.
(38) Life threatening Osler-Rendu-Weber telangiectasia
Authors: I.H. Coulson, V. Moore-Gillon, B. Pickard
Journal: British Journal of Dermatology (1985)

Journal Article (38) Life threatening Osler‐Rendu‐Weber telangiectasia Get access I.H. Coulson, I.H. Coulson St George's Hospital, London SW17 Search for other works by this author on: Oxford Academic Google Scholar V. Moore‐Gillon, V. Moore‐Gillon St George's Hospital, London SW17 Search for other works by this author on: Oxford Academic Google Scholar B. Pickard B. Pickard St George's Hospital, London SW17 Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 113, Issue s29, 1 July 1985, Pages 83–84, https://doi.org/10.1111/j.1365-2133.1985.tb13053.x Published: 01 July 1985