tbuckley/cabot-search huggingface dataset:
PTU-125 Biochemical Patterns Of Presentation In Primary Sclerosing Cholangitis: Younger Age At Onset Is Associated With A Lower Alp/ast Ratio
Authors: PJ Trivedi, J Robinson, T Wright, T Bruns, K-K Li, H Shah, D Adams, J Ferguson, G Hirschfield
Journal: Gut (2014)

<h3>Introduction</h3> Autoimmune sclerosing cholangitis is the paediatric term applied to children presenting with features of autoimmune hepatitis and sclerosing cholangitis. We hypothesised that if this inflammatory phenotype was a continuum, young adults with primary sclerosing cholangitis (PSC) would also have a more inflammatory presentation. <h3>Methods</h3> We undertook a retrospective case-note review of our patients with an established diagnosis of PSC presenting between 2003–2013 (n = 116). Clinical characteristics and laboratory parameters were collected, and differences in disease phenotype correlated with age at presentation (SPSSv21). <h3>Results</h3> The median age of disease presentation in our cohort was 44 years (IQR:25–56). Although there was no significant correlation between patient age and mode of disease presentation, younger age was more commonly associated with lower baseline serum ALP (Spearman's <i>rho </i>= 0.239; <i>P </i>= 0.011). Patient age negatively correlated with ALP:AST ratio (<i>rho </i>= 0.252; <i>P </i>= 0.008); however, there was no correlation with serum AST, bilirubin, albumin, platelet count, INR, IgG titre or ANA/ASMA status. Using quartile cut-points in order to compare extremes of age, individuals presenting below the age of 25 (Q4; 7.6; 3.2–13.0) (<i>P </i>= 0.023). Age &lt;25 at disease presentation was more often associated with an ALP:AST ratio &lt;1.5 (11/25 [44%] vs. 4/25; [16%], <i>P </i>= 0.017). There were no significant differences in IBD phenotype, number of patients meeting transplantation or median time to transplant. <h3>Conclusion</h3> Younger patients more commonly have a lower ALP/AST ratio at disease presentation, and may indicate a more 'inflammatory' PSC phenotype. <h3>Disclosure of Interest</h3> None Declared.
Virus-specific cytotoxic T-lymphocyte responses select for amino-acid variation in simian immunodeficiency virus Env and Nef
Authors: David T. Evans, David H. O'Connor, Peicheng Jing, John L. Dzuris, John Sidney, Jack da Silva, Todd M. Allen, Helen Horton, John E. Venham, Richard A. Rudersdorf, Thorsten Vogel, C. David Pauza, Ronald E. Bontrop, Robert DeMars, Alessandro Sette, Austin L. Hughes, David I. Watkins
Journal: Nature Medicine (1999)
EXPERIENCE WITH OVER ON THOUSAND CASS OF A FORM OF CHRONIC URETHRITIS
Authors: SYLVAN H LIKES
Journal: JAMA (1913)

It is generally conceded that there are few conditions more nerve-racking or distressing to a person than an infection with a venereal disease. This is particularly manifested and emphasized in those afflicted with a long-standing urethritis. The serious nature of the maladies which may be acquired through sexual intercourse is being daily impressed on the public by the dissemination of literature bearing on this subject. Most men are already cognizant of these dangers, however, either in having been victims themselves, or from knowing the experience of others. The patient has to bear not only the physical suffering incident to venereal diseases, but also the mental distress due to the embarrassing secrecy of the situation, to the objectionable restrictions, which frequently cause humiliation, to fear of exposure, to the danger of infecting others, and to the possibility of the many painful and serious complications. However well-recognized these facts may be, they
Inventing a new diagnostic test for vaginal infection
Authors: T C O'Dowd, N Bourne
Journal: BMJ (1994)

Bacterial vaginosis, which is underdiagnosed in clinical practice, has a characteristic fishy smell because of production of diamines. This smell is the basis of a visual rapid diagnostic test that is technically simple to perform. The test has been patented in Europe and America, and a licence agreement has been negotiated. This paper describes the process from idea to invention to patenting and licensing. The combined costs of research and patenting were met by a multinational company in return for rights to exploit the patent invention. The process has taken nine years and has needed clinical, scientific, legal, and commercial input to get the test to the marketplace.
The Bone Marrow Microenvironment as a Tumor Sanctuary and Contributor to Drug Resistance
Authors: Mark B. Meads, Lori A. Hazlehurst, William S. Dalton
Journal: Clinical Cancer Research (2008)

Abstract The bone marrow microenvironment facilitates the survival, differentiation, and proliferation of hematopoietic cells. These cells are supported by fibroblast-like bone marrow stromal cells, osteoblasts, and osteoclasts which secrete soluble factors and extracellular matrix proteins that mediate these functions. This rich environment serves as a safe haven not only for normal and malignant hematopoietic cells, but also for epithelial tumor cells that metastasize to bone, offering protection from chemotherapeutic agents by common mechanisms. Soluble factors produced in the bone marrow, such as stromal cell–derived factor-1 and interleukin-6, mediate homing, survival, and proliferation of tumor cells, and integrin-mediated adhesion sequesters tumor cells to this protective niche. Environment-mediated drug resistance includes a combination of soluble factors and adhesion, and can be subdivided into soluble factor–mediated drug resistance and cell adhesion–mediated drug resistance. Because it is induced immediately by the microenvironment and is independent of epigenetic or genetic changes caused by the selective pressure of drug exposure, environment-mediated drug resistance is a form of de novo drug resistance. In this form of drug resistance, tumor cells are transiently and reversibly protected from apoptosis induced by both chemotherapy and physiologic mediators of cell death. This protection allows tumor cells to survive the insult of chemotherapy, leading to minimal residual disease, and thereby increases the probability for the development of acquired drug resistance.
Abstract IA9: The molecular pathology of adenocarcinoma versus histopathological classification
Authors: Elisabeth Brambilla
Journal: Clinical Cancer Research (2012)

Abstract Recent therapeutic advances have led to a revolution in the lung cancer field in discovering therapeutically tractable oncogene dependency with major implications for patient evaluation and approach to diagnosis. A recently published IASLC/ATS/ERS classification of lung adenocarcinoma addresses these issues fully based on the molecular features of histological subtypes of adenocarcinoma (1). As deduced from their molecular signatures, pathological patterns are the most achieved translation of the full genomic space (expression profiles, gene copy number alterations, and likely epigenetics space …). Therefore the functional clusters of genes defining a phenotypic population dictates the survival and contains targets of therapies in adenocarcinoma supporting the contention that each of the pathological and molecular features contains this information (2, 3). The new classification of adenocarcinoma has a high prognostic interest validated on further independent series of the literature (4). Molecular pathology recapitulates both differentiation markers and biomarkers of therapeutic sensitivity. A stepwise accumulation of genetic and molecular abnormalities is sustaining the morphological transition between preinvasive and invasive and metastatic process in adenocarcinoma. Now that lung cancer therapies personalized for individual patients is based on the histologic type of lung cancer and molecular status, the pathologist role using the knowledge on molecular pathology is to allow the histomolecular classification on small biopsies and cytology, the only specimens available in advanced treatable cases of adenocarcinoma (5). A few differentiation markers (TTF-1, P63, P40, mucines) met the need for subclassification of cases with adenocarcinoma components (adenocarcinoma per se, large cell carcinoma, sarcomatoid carcinoma and NSCLC/NOS) driving their molecular analysis (6). TTF-1 positive solid and cribriform tumor with signet ring are strongly associated with susceptibility for EML4-ALK fusion for ALK positivity candidate for crizotinib therapy, whereas Ras mucinous adenocarcinoma (previously mucinous BAC) are essentially TTF-1 negative, amphiregulin positive with IGFR activated pathway which are strongly resistant to gefitinib alone but are restored to sensitivity by IGFR inhibitors (7). Articulation between molecular pathology and histopathological features will in the future be the first organizers of therapeutical decisions (7). Conclusion: As the molecular changes directly influence the therapy today and even more in the future, we think this should be reflected in the taxonomy as well as in the term given in the WHO classification. Histopathological classification would tend to predict that the molecular characteristics of the tumors together with their immunohistochemical and morphological appearance will dictate therapy in the future. Gefitinib is less effective in non adenocarcinoma NSCLC harboring EGFR mutations (8).
Abstract 4000: Genistein-induced reduction of Wnt/beta-catenin pathway activity in colorectal cancer cell lines correlates with inhibition of proliferation and colony growth in soft agar .
Authors: Sofya Pintova, Kestutis Planoutis, Marina Planutiene, Randall F. Holcombe
Journal: Cancer Research (2013)

Abstract Introduction. The majority of colorectal cancers (CRC) have mutationally-driven constitutive activation of the Wnt pathway. Despite this, tumor cells remain responsive to Wnt signals arising at the cell membrane through the interaction of extracellular Wnt ligands and cell surface frizzled receptors; the strength of the Wnt signal can be modified by Wnt pathway inhibitors (sFRP) in the tumor microenvironment. Genistein, a natural product from soy, is known to remove epigenetic blockage of sFRP promoters and decrease nuclear beta-catenin expression, a marker for Wnt pathway activation. In this study we have examined the effect of genistein on Wnt throughput in CRC cell lines and on proliferation in tissue culture and growth in soft agar. Methods. Human CRC cell lines HT29, DLD1 and RKO were transfected with Wnt/beta-catenin reporter plasmids and treated with different concentrations of genistein. Pathway activity was measured using a super TOP-flash luminescence reporter construct. Proliferation was estimated with an MTT assay. A soft agar assay was utilized to define non-adherent colony formation. Results. Genistein reduced proliferation of HT29 and DLD1 at 50uM, with an inhibitory P50 at 100uM. RKO cells were inhibited at lower concentrations. Inhibition of soft agar colony growth occurred at similar concentrations. Wnt/beta-catenin activity was significantly inhibited at 75uM for HT29 (p=0.025) and at 50uM for DLD1. The reduction in proliferation and colony growth correlated with reduced Wnt signaling, with the latter most strongly correlated (R2=0.81 vs. 0.47 for the former). Cells growing independently of anchorage were more sensitive to genistein treatment than those attached to the plastic : colony counts decreased for RKO 8-fold at 50 uM while proliferation on plastic decreased less than 4x; colony counts decreased for HT29 7-fold for at 100 uM while proliferation on plastic decreased less than 2x. Conclusions. Genistein reduces Wnt/beta-catenin activity in CRC cell lines; this reduction correlates with cell proliferation in vitro and with soft agar colony growth. Cells growing in an anchorage-independent fashion appear more sensitive to genistein treatment. Further investigation into the mechanisms of this effect in CRC is ongoing. These data suggest that genistein may be a useful adjunctive therapy for patients with CRC. Citation Format: Sofya Pintova, Kestutis Planoutis, Marina Planutiene, Randall F. Holcombe. Genistein-induced reduction of Wnt/beta-catenin pathway activity in colorectal cancer cell lines correlates with inhibition of proliferation and colony growth in soft agar . [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4000. doi:10.1158/1538-7445.AM2013-4000
POEMs: Patient-Oriented Evidence That Matters
Authors: Allen F. Shaughnessy
Journal: Annals of Internal Medicine (1997)

Letters15 April 1997POEMs: Patient-Oriented Evidence That MattersAllen F. Shaughnessy, PharmD and David C. Slawson, MDAllen F. Shaughnessy, PharmDHarrisburg Family Practice Residency, Harrisburg, PA 17105University of Virginia, Charlottesville, VA 22908 and David C. Slawson, MDHarrisburg Family Practice Residency, Harrisburg, PA 17105University of Virginia, Charlottesville, VA 22908Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-126-8-199704150-00032 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:Fleming and DeMets [1] do an excellent job of pointing out the inadequacy of surrogate markers as appropriate outcomes for phase III trials. Surrogate markers are also inappropriate for clinical practice, yet they serve as the foundation on which many of the daily decisions in medicine are made.Managed care is forcing clinicians to re-evaluate their decision making with well-focused questions on outcomes of care. Many clinicians try to deflect these queries as merely being based on finances. These questions, however, force us to examine our practices to determine whether our interventions truly are in the best ...References1. Fleming TR, DeMets DL. Surrogate end points in clinical trials: are we being misled? Ann Intern Med. 1996; 125:605-13. Google Scholar2. Slawson DC, Shaughnessy AF, Bennett JH. Becoming a medical information master: feeling good about not knowing everything. J Fam Pract. 1994; 38:505-13. Google Scholar3. Riffenburgh RH. Reverse gullibility and scientific evidence. Arch Otolaryngol Head Neck Surg. 1996; 122:600-1. Google Scholar Author, Article, and Disclosure InformationAffiliations: Harrisburg Family Practice Residency, Harrisburg, PA 17105University of Virginia, Charlottesville, VA 22908 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byTesting polyp resection techniques: Are we asking the clinically relevant questions?Quality and Outcome Measures for Medical RehabilitationQuality and Outcome Measures for Medical RehabilitationCommunicating statin evidence to support shared decision-makingSufficiently Important DifferenceEmerging Concepts in the Treatment of Myofascial Pain: A Review of Medications, Modalities, and Needle-based InterventionsUse of a fermented dairy probiotic drink containing Lactobacillus casei (DN-114 001) to decrease the rate of illness in kids: the DRINK study A patient-oriented, double-blind, cluster-randomized, placebo-controlled, clinical trialReihe Evidenzbasierte Chirurgie 15 April 1997Volume 126, Issue 8Page: 667KeywordsBiomarkersClinical trialsDecision makingPatients Issue Published: 15 April 1997 Copyright & PermissionsCopyright © 1997 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Multiple Sclerosis: A Critical Conspectus
Authors: Stuart A. Schneck
Journal: JAMA (1978)

In this volume, Dr E. J. Field has assembled an international group of multiple sclerosis (MS) investigators who attempt to summarize the short-comings of present investigative approaches to the etiology and pathogenesis of this disorder. The hope is expressed that examination of many basic premises that guide current MS research may lead to new and fruitful lines of inquiry. Field himself, in an interesting introduction, discusses important difficulties with MS in terms of diagnosis and clinical course, epidemiology, pathology, geriatrics, and immunology. At the end of the volume, he describes several laboratory tests for the diagnosis of MS, which involve the interaction between unsaturated fatty acids, macrophages, and erythrocytes. The reader should be aware that claims made for the specificity of these tests are not accepted by many workers. Between these chapters, there is an excellent section on clues from clinical features by Fog, two long articles on epidemiology by
Purinergic inhibition of GABA and glutamate release in the thalamus: Implications for thalamic network activity
Authors: Daniel Ulrich, John R. Huguenard
Journal: Neuron (1995)

Adenosine is a CNS depressant with both pre- and postsynaptic actions. Presynaptically, adenosine decreases neurotransmitter release in the hippocampus but only at excitatory terminals. In the thalamus, however, we show that, in addition to its actions at excitatory synapses, adenosine strongly suppresses monosynaptic inhibitory currents both in relay cells of the thalamic ventrobasal complex (VB) and in inhibitory neurons of the nucleus reticularis thalami (nRt). A concomitant increase in transmission failures and results coefficient of variation analysis are both consistent with a presynaptic mechanism. Pharmacological manipulations support an A1 receptor-mediated process. Slow thalamic oscillations induced in vitro by extracellular stimulation and recorded with extracellular multiunit electrodes in VB and nRt are dampened by adenosine without affecting their periodicity. We conclude that adenosine can presynaptically down-regulate inhibitory postsynaptic responses in thalamus and exert robust antioscillatory effects, likely by synergistic depression of both excitatory and inhibitory neurotransmitter release.
Comparison of Hydroflumethiazide and Meralluride
Authors: Harry Gold
Journal: JAMA (1961)

This communication describes an exercise in quantitative human pharmacology having characteristics uncommon in clinical trials: measurement of those effects for which the drug is intended; comparison with a standard in each patient; comparison of doses with maximal effect of the respective drugs; data emerging out of a highly effective regimen of treatment (identity of treatment and experiment); determination of the ratio in each test-patient obtained after the first four daily doses supplying a 24-hour weight change; and expression of the reliability of the conclusion in terms of statistical devices (sign test and confidence limits). Hydroflumethiazide (Saluron) in 0.4 and 0.8 gm. oral doses and meralluride (Mercuhydrin) in 2 cc. intramuscular doses compared in this way showed the hydroflumethiazide to have 67% the efficacy of meralluride in clearing edema as against 40% for chlorothiazide in a previous study.
Every system is designed to get the results it gets
Authors: G. T O'Connor
Journal: BMJ (1997)

Patients and public assume that the surgeon is responsible for the quality of surgical care and that they are protected from substandard care by quality monitoring conducted by professional bodies. These bodies are often presented with evidence suggesting suboptimal clinical care and rule on its validity. Such is the case of a cardiothoracic surgeon from Bristol who has been cited for having unacceptably poor results which comes before Britain's regulatory body, the General Medical Council, next week (in a case expected to last four months). These cases occur with some frequency and often concern high visibility specialties with easy to count outcomes. Yet causal attribution is difficult since most clinicians provide care in complex settings over which individuals exert only limited control.

In cardiac care the skills of the anesthesiologist, perfusionist, cardiac intensive care nurse, and others also affect the outcomes of care. Their individual competence is not sufficient: they must also work well together. It is the product of their individual work—not the sum—that the patient experiences. Removing one “outlier” surgeon from practice will, at most, influence the second decimal place of the national cardiac surgery mortality rate. It may be necessary for the public welfare that we do this, but the public should not be led to believe that such actions do much to improve the …
c-Jun Reprograms Schwann Cells of Injured Nerves to Generate a Repair Cell Essential for Regeneration
Authors: Peter J. Arthur-Farraj, Morwena Latouche, Daniel K. Wilton, Susanne Quintes, Elodie Chabrol, Ambily Banerjee, Ashwin Woodhoo, Billy Jenkins, Mary Rahman, Mark Turmaine, Grzegorz K. Wicher, Richard Mitter, Linda Greensmith, Axel Behrens, Gennadij Raivich, Rhona Mirsky, Kristján R. Jessen
Journal: Neuron (2012)

SummaryThe radical response of peripheral nerves to injury (Wallerian degeneration) is the cornerstone of nerve repair. We show that activation of the transcription factor c-Jun in Schwann cells is a global regulator of Wallerian degeneration. c-Jun governs major aspects of the injury response, determines the expression of trophic factors, adhesion molecules, the formation of regeneration tracks and myelin clearance and controls the distinctive regenerative potential of peripheral nerves. A key function of c-Jun is the activation of a repair program in Schwann cells and the creation of a cell specialized to support regeneration. We show that absence of c-Jun results in the formation of a dysfunctional repair cell, striking failure of functional recovery, and neuronal death. We conclude that a single glial transcription factor is essential for restoration of damaged nerves, acting to control the transdifferentiation of myelin and Remak Schwann cells to dedicated repair cells in damaged tissue.Highlights•Schwann cell c-Jun is a master regulator of the PNS injury response•c-Jun activates a defined repair program in Schwann cells of damaged nerves•c-Jun controls transdifferentiation of differentiated Schwann cells to repair cells•Schwann cell c-Jun is essential for neuronal survival and functional recovery
Acute phase reactants ceruloplasmin and haptoglobin and their relationship to plasma prostaglandins in rabbits bearing the VS2 carcinoma.
Authors: E F Voelkel, L Levine, C A Alper, A H Tashjian
Journal: The Journal of Experimental Medicine (1978)

Results of previous studies have shown that the VX2 carcinoma in rabbits synthesizes large amounts of prostaglandin E2 (PGE2). PGE2 secreted by the tumor is rapidly metabolized and can be measured in plasma as the metabolite 13,14-dihydro-15-keto-PGE2 (PGE2-M). We have previously proposed that the hypercalcemia that occurs in rabbits bearing the VX2 carcinoma is due to excessive secretion of PGE2 by the tumor and its subsequent action on the skeleton as a bone resorption-stimulating factor. In the course of these studies, we noted that the plasma of rabbits bearing the VS2 carcinoma became blue about 1 wk after tumor implantation. The intensity of the color increased markedly thereafter. We therefore measured ceruloplasmin in plasma by both chemical and immunological assay methods. Plasma ceruloplasmin and PGE2-M rose in parallel (within 7-10 days) and preceded by 7-10 days the development of hypercalcemia. 2 wk after tumor implantation, plasma PGE2-M and ceruloplasmin had risen about 20- and 6-fold, respectively, while the rise in plasma calcium was just beginning. Indomethacin, an inhibitor of prostaglandin synthesis, given from the time of tumor implantation prevented completely the hypercalcemia and largely inhibited the rise in ceruloplasmin. When given after hyperprostaglandinemia had developed, indomethacin produced a fall in both PGE2-M and ceruloplasmin. A rise in plasma haptoglobin concentrations similar to that seen for ceruloplasmin was also observed. No changes in plasma albumin concentrations occurred. We conclude that the acute phase reactants ceruloplasmin and haptoglobin rise rapidly in the plasma of rabbits bearing the VX2 carcinoma, and that this increase is related to arachidonic acid metabolism in these animals. It is possible that arachidonic acid metabolites also play a role in the elevations of these two plasma proteins observed in certain patients with malignant tumors.