tbuckley/cabot-search huggingface dataset:
Government is urged to stop claiming spending on NHS has risen
Authors: G. Iacobucci
Journal: BMJ (2012)

<h3>Objectives</h3> To investigate how the genetic susceptibility gene <i>DIO2</i> confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches. <h3>Methods</h3> Epigenetically regulated expression of <i>DIO2</i> was explored by assessing methylation of positional CpG-dinucleotides and the respective <i>DIO2</i> expression in OA-affected and macroscopically preserved articular cartilage from end-stage OA patients. In a human in vitro chondrogenesis model, we measured the effects when thyroid signalling during culturing was either enhanced (excess T3 or lentiviral induced <i>DIO2</i> overexpression) or decreased (iopanoic acid). <h3>Results</h3> OA-related changes in methylation at a specific CpG dinucleotide upstream of <i>DIO2</i> caused significant upregulation of its expression (β=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by <i>DIO2</i> rs225014 risk allele carriers (β=5.58, p=0.0006). During in vitro chondrogenesis, <i>DIO2</i> overexpression resulted in a significant reduced capacity of chondrocytes to deposit extracellular matrix (ECM) components, concurrent with significant induction of ECM degrading enzymes (ADAMTS5, MMP13) and markers of mineralisation (ALPL, COL1A1). Given their concurrent and significant upregulation of expression, this process is likely mediated via HIF-2α/RUNX2 signalling. In contrast, we showed that inhibiting deiodinases during in vitro chondrogenesis contributed to prolonged cartilage homeostasis as reflected by significant increased deposition of ECM components and attenuated upregulation of matrix degrading enzymes. <h3>Conclusions</h3> Our findings show how genetic variation at <i>DIO2</i> could confer risk to OA and raised the possibility that counteracting thyroid signalling may be a novel therapeutic approach.
Validation of Seattle Heart Failure Model for mortality risk prediction in patients treated with cardiac resynchronization therapy
Authors: François Regoli, Francesca Scopigni, Francisco Leyva, Maurizio Landolina, Stefano Ghio, Massimo Tritto, Leonardo Calò, Catherine Klersy, Angelo Auricchio
Journal: European Journal of Heart Failure (2012)

Survival prediction by the Seattle Heart Failure Model (SHFM) of patients treated with cardiac resynchronization therapy (CRT) remains ill defined. The performance of the SHFM in this clinical setting was therefore evaluated.Data from 1309 consecutive CRT patients (five centres) were collected retrospectively; 1139 of these patients were considered for analysis. Three-hundred and seven deaths occurred over 40.1 months (interquartile range 25.2-60.0 months; mean event rate 9.7%/year; survival of 89, 81, and 64% at 1, 2, and 5 years). Kaplan-Meier event-free survival analysis stratified according to tertile of SHFM score was significant (log rank test P < 0.001). High-risk tertile (T1) survival was 82, 67, and 46% at 1, 2, and 5 years, respectively. Observed compared with SHFM-predicted survival was 0.11 vs. 0.08, 0.19 vs. 0.16, and 0.36 vs. 0.36, at 1, 2, and 5 years. Model discrimination by c-statistic was 0.64; the logistic models' area under the receiver operating characteristic curve (AUC-ROC) of risk tertiles was 0.66, 0.68, and 0.67, at 1, 2, and 5 years. Compared with the other two groups, T1 was globally more compromised. Within the T1 group, independent predictors of death were male gender, ischaemic heart failure aetiology, lower body weight, and CRT pacemaker.SHFM performance was found to be modest, tending to overestimate survival. However, SHFM identified a high-risk, globally more compromised patient subgroup, hence supporting a comprehensive approach, which should include nutritional, metabolic, and immunological aspects, as well as defibrillator back-up.
Combination thymosin alpha 1 and lymphoblastoid interferon treatment in chronic hepatitis C.
Authors: G Rasi, D DiVirgilio, M G Mutchnick, F Colella, P Sinibaldi-Vallebona, P Pierimarchi, B Valli, E Garaci
Journal: Gut (1996)

Monotherapy for chronic hepatitis C using interferon (IFN) results in a very small proportion of patients exhibiting a sustained response. Clinical trials assessing the benefit of combination drug therapy may provide evidence of improved treatment response over that seen with single drug treatment.To assess the response in patients with chronic hepatitis C to one year of combination treatment: thymosin alpha 1 (T alpha 1), 1 mg twice weekly, and lymphoblastoid (L)-IFN, 3 MU thrice weekly.Fifteen patients with serum HCV RNA positive chronic hepatitis C were studied. Eleven patients were treatment naive and four had failed previous standard IFN therapy. Thirteen patients were HCV RNA serotype 1b. All patients were given combination T alpha 1 and L-IFN therapy for one year with a six month follow up period.Six months after initiation of treatment seven patients (47%) were sera HCV RNA negative and at completion of the one year treatment 11 (73%), including two who had failed previous standard IFN treatment, had negative serum HCV RNA. Six months after treatment, six patients (40%), including five with HCV type 1b, showed a sustained response characterized by a negative serum HCV RNA.The results of this open label trial suggest that there may be a potential benefit to combining an immune modulator (T alpha 1) with an antiviral (IFN) in the treatment of chronic hepatitis C. Verification of the observations in this study require completion of a randomised controlled study.
Laryngeal Tuberculosis or Tumor
Authors: JAMES O. MORSE
Journal: Annals of Internal Medicine (1974)

Comments1 November 1974Laryngeal Tuberculosis or TumorJAMES O. MORSE, M.D.JAMES O. MORSE, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-81-5-711 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: Dr. Rohwedder has described very well the picture of upper respiratory tract tuberculosis (1). Several tuberculous larynxes should be spared unnecessary biopsies as a result of this paper, and some laryngoscopists may even escape conversion of their tuberculin reactions. We have recently been troubled by a case in which the opposite course occurred, with unfortunate results.A 50-year-old alcoholic man was admitted with far-advanced pulmonary tuberculosis. Because of hoarseness, indirect laryngoscopy was done 6 days after admission. The epiglottis was injected, thickened, and covered with a whitish exudate. The arytenoids were injected and thickened, but the remainder...Reference1. ROHWEDDER J: Upper respiratory tract tuberculosis. Sixteen cases in a general hospital. Ann Intern Med 80:708-713, 1974 LinkGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: JAMES O. MORSE, M.D.Affiliations: Clinical Chest Section Veterans Administration Hospital Tucson, Arizona 85723 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byLaryngeal tuberculosis in the United States of America: A forgotten diseaseDisfonía y tuberculosis laríngea: presentación de dos casos y revisión de la bibliografíaTuberculosis laríngea: estudio de 11 casosVideostroboscopic Findings in Laryngeal TuberculosisOral tuberculosisThe presentation of laryngeal tuberculosisCase 51-1983Laryngeal tuberculosis in TanzaniaThe changing pattern of laryngeal tuberculosisTuberculosis of the Larynx Masquerading as Carcinoma 1 November 1974Volume 81, Issue 5Page: 711-712KeywordsAlcoholicsBiopsyLarynxRespiratory systemTuberculin ePublished: 1 December 2008 Issue Published: 1 November 1974 PDF downloadLoading ...
P3-16-18: Phase 2, Open-Label Study of EZN-2208 (PEG-SN38) in Patients with Previously Treated Metastatic Breast Cancer.
Authors: JA O'Shaughnessy, CRC Osborne, MA Steinberg, FA Holmes, HS Kim, DM Kocs, PD Richards, SJ Vukelja, N Berkowitz, A Buchbinder
Journal: Cancer Research (2011)

Abstract Background EZN-2208 is a water-soluble PEGylated conjugate of SN38 that results in parenteral delivery, increased solubility, higher exposure, and longer apparent half-life of SN38, as well as more profound deoxyribonucleic acid (DNA) damage and inhibition of angiogenesis. EZN-2208 results in prolonged exposure of tumors to SN38 via preferential accumulation of EZN-2208 in the tumor and prolonged release of SN38 in the blood. Methods: This trial evaluated EZN-2208 delivered as a 1-h IV infusion weekly for 3 wks in 4-wk cycles. The primary objective was to determine the overall response rate (RR) in female patients with metastatic breast cancer (MBC) who had received prior adjuvant or metastatic therapy with either 1) anthracycline and taxane (AT) or 2) anthracycline, taxane, and capecitabine (Xeloda®) (ATX). Secondary objectives included evaluation of RR based on tumor receptor status, duration of response, progression-free survival (PFS), overall survival (OS), and safety and toxicity. Response was evaluated using RECIST (v1.1). Results: 148 patients received EZN-2208 in the AT (n=65; median age = 56 y [31-84 y]) or ATX (n=83; median age = 55 y [36-83 y]) cohorts. All 65 patients in the AT cohort had received 0–2 lines of prior cytotoxic therapy for MBC; for the ATX cohort, 31 patients (37%) had received 0–2 prior lines of cytotoxic therapy for MBC, 50 patients (60%) had received 3–4 prior lines, and 2 patients (2%) had received 5 prior lines. Preliminary results follow; final data will be presented at the meeting. Median (range) cycles of EZN-2208 was 2.3 (0.3-14) for AT and 2 (0.3-15) for ATX. Best overall response is shown in the table. RR (PR+uPR) was 22% for AT and 10% for ATX. Median (95% CI) time to progression was 3.8 mo (3.6−7.4) for AT and 3.3 mo (1.8−3.7) for ATX. Median (95% CI) duration of response was 4.0 mo (3.7−5.6) for AT and 5.2 mo (1.9-..) for ATX. 6-mo PFS (95% CI) was 34% (19%-50%) for AT and 19% (9%-29%) for ATX. Median PFS (95% CI) was 3.8 mo (2.7−5.6) for AT and 2.9 mo (1.83.7) for ATX. Median OS (95% CI) was 9.1 mo (6.1−12.7) for AT and 7.9 mo (6.4−12.9) for ATX. Grade 3 or 4 drug-related adverse events (&amp;gt;10% of patients in either arm) included neutropenia (43%, 33%), diarrhea (11%, 8%), and leukopenia (11%, 6%). Conclusions: EZN-2208 is active in patients with previously treated MBC. The activity is similar regardless of ER status and is promising in the TNBC population. The safety profile of EZN-2208 is acceptable with good tolerability in most patients. Further evaluation of EZN-2208 in this population is warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-18.
Management of medically unexplained symptoms
Authors: Marianne Rosendal, Frede Olesen, Per Fink
Journal: BMJ (2004)

Includes diagnosis, specific treatments, and appropriate communication 

I n all parts of our healthcare system we meet patients presenting with physical symptoms that lack an obvious organic basis. The terms used to describe such symptoms—medically unexplained symptoms or functional somatic symptoms—are purely descriptive and do not imply psychogenesis. Other names such as somatisation and somatoform disorder are also being used but imply different definitions.1–3 Patients with medically unexplained symptoms do not fit into the existing framework of a biomedical model that tends to focus on the exclusion of physical disease. However, the exclusion of relevant physical disease may not in itself cure the patient. He or she may still feel ill and seek medical care. Medically unexplained symptoms therefore represent a clinical problem that must be taken seriously.1–4 General practice has a key role in the management of this clinical problem as at least 20-30% of primary care patients have medically unexplained symptoms. Current evidence indicates that medical care of medically unexplained symptoms should include improvements in three interrelated elements—diagnosis, specific treatment strategies, and communication.

The concept of medically unexplained symptoms comprises a …
The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of alpha v beta 3 in smooth muscle cell migration to osteopontin in vitro.
Authors: L Liaw, M P Skinner, E W Raines, R Ross, D A Cheresh, S M Schwartz, C M Giachelli
Journal: Journal of Clinical Investigation (1995)

Osteopontin is an arginine-glycine-aspartate containing acidic glycoprotein postulated to mediate adhesion, migration, and biomineralization in diverse tissues. The mechanisms explaining this multifunctionality are not well understood, although it is known that one osteopontin receptor is the alpha v beta 3 integrin. In this work, we studied human smooth muscle cells varying in alpha v beta 3 levels to identify additional osteopontin receptors. We report that, in addition to alpha v beta 3, both alpha v beta 5 and alpha v beta 1 are osteopontin receptors. Moreover, the presence or absence of alpha v beta 3 on the cell surface altered the adhesive and migratory responses of smooth muscle cells to osteopontin. Adhesion of alpha v beta 3-deficient cell populations to osteopontin was only half that of cells containing alpha v beta 3, and migration toward an osteopontin gradient in the Boyden chamber was dependent on cell surface alpha v beta 3. Although alpha v beta 3-deficient smooth muscle cells were unable to migrate to osteopontin, they did migrate significantly in response to vitronectin and fibronectin. These findings represent the first description of alpha v beta 5 and alpha v beta 1 as osteopontin receptors and suggest that, while adhesion to osteopontin is supported by integrins containing beta 1, beta 3, and beta 5, migration in response to osteopontin appears to depend on alpha v beta 3. Thus, interaction with distinct receptors is one mechanism by which osteopontin may initiate multiple functions.
Book Review Transfusion Microbiology Edited by John A.J. Barbara, Fiona A.M. Regan, and Marcela C. Contreras. 390 pp., illustrated. New York, Cambridge University Press, 2008. $160 (cloth); $128 (e-book). 978-0-521-45393-6 (cloth); 978-0-511-42112-9 (e-book).
Authors: John D. Roback
Journal: New England Journal of Medicine (2009)
HEPARIN AS A PROPHYLACTIC AGAINST THROMBOSIS
Authors: CLARENCE CRAFOORD
Journal: JAMA (1941)

The use of heparin as prophylactic against thrombosis has arisen through our increased knowledge of this substance gained during the last few years. The latest developments in this field have been reviewed in two monographs of recent date. 1 The chemical nature of heparin is known. Being a mucoitin polysulfuric acid with not less than about 40 per cent of sulfuric acid, the heparin polysaccharide possesses an exceedingly high negative electric charge which enables it to react with some of the components of the coagulation system, preventing the coagulation of the blood. In the body it functions like a hormone, lessening the coagulability of the blood. Like other hormones, it is produced by a special kind of cells, the mast cells of the connective tissue, known to be located mainly in the neighborhood of the smaller blood vessels. The metachromatic granules of these cells consist of heparin. From these cells
Efficacy and safety of wet‐wrap dressings in children with severe atopic dermatitis: influence of corticosteroid dilution
Authors: A. Wolkerstorfer, R.L. Visser, F.B. De Waard, None Van Der Spek, P.G.H. Mulder, A.P. Oranje
Journal: British Journal of Dermatology (2000)

Background The wet-wrap treatment involves emollients or corticosteroid dilutions under occlusive wet dressings, and has been reported to be highly effective in severe refractory atopic dermatitis (AD). Objectives To investigate the influence of different corticosteroid dilutions on the efficacy and hypothalamic–pituitary–adrenal (HPA) axis suppression in children with severe refractory AD having wet-wrap dressings. Methods Eighteen children were treated with a 50% dilution of fluticasone propionate (FP) 0·05% cream for 2 weeks. In another five children a side-to-side comparison was conducted with 10%, 25% and 50% dilutions of FP cream under wet wrap. A third group of eight children was treated with 0% (= emollient), 5%, 10% or 25% dilutions of FP cream applied on the whole body under wet wrap. Results After 1 week, a major improvement averaging 74% was observed, without apparent differences between 5%, 10% or 25% dilutions of FP cream under wet wrap, with less improvement in the second week of treatment. The first and second group of children showed HPA axis suppression in only three of 23 children using measurements of 09·00 h serum cortisol after 2 weeks. The third group of children showed HPA axis suppression, as indicated by 06·00 h serum cortisol levels, which was related to the absolute amount of FP applied. Conclusions This suggests that weaker corticosteroid dilutions had comparable high efficacy, but lower risk of HPA axis suppression.
Immunoglobulin G subclass distribution of autoantibodies in systemic sclerosis, primary biliary cirrhosis, and overlap syndromes.
Authors: M A French, R M Bernstein
Journal: Annals of the Rheumatic Diseases (1987)

The IgG subclass reactivities of six anticellular antibodies were measured by indirect immunofluorescence on HEp2 cells using murine monoclonal antibodies to the four human IgG subclasses. Patients with scleroderma, primary biliary cirrhosis (PBC), systemic lupus erythematosus, and mixed connective tissue disease were studied. Anticentromere antibody (ACA) was virtually all IgG1 and 3; antibody to multiple nuclear dots (NSpI) was IgG1, 2, and 3; antimitochondrial antibody was mainly IgG2 and 3; nucleolar staining was varied in subclass reactivity but most often IgG4; the diffusely grainy staining associated with Scl-70 antibody was chiefly IgG1; and the speckled pattern associated with anti-RNP antibody was always IgG1 and 4, with IgG2 and 3 in some cases. These data fail to support the hypothesis that the various patterns of autoimmune disease reflect differences in the biological properties of the associated antibodies. The prominence of IgG2 in antibodies associated with PBC suggests the possibility of an immune response independent of T cells in that condition. Differential subclass staining showed an unexpectedly high frequency of antibody to multiple nuclear dots in ACA positive sera, and such patients (all with CREST syndrome) could be at increased risk of developing PBC later.
Altered Bone Morphogenetic Protein and Transforming Growth Factor-β Signaling in Rat Models of Pulmonary Hypertension
Authors: Lu Long, Alexi Crosby, Xudong Yang, Mark Southwood, Paul D. Upton, Dae-Kee Kim, Nicholas W. Morrell
Journal: Circulation (2009)

Background— Recent genetic studies have highlighted the role of the bone morphogenetic protein (BMP)/transforming growth factor (TGF)-β signaling pathways in the pathogenesis of familial pulmonary arterial hypertension (PAH). It remains unclear whether alterations in these pathways contribute to other forms of pulmonary hypertension and to what extent these changes can be exploited for therapeutic intervention. Methods and Results— We studied BMP/TGF-β signaling in 2 rat models of PAH due to chronic hypoxia and monocrotaline. In both models, there was a significant reduction in lung BMP type IA receptor and BMP type II receptor mRNA expression, although these changes were more pronounced in the monocrotaline model. This was accompanied by a reduction in lung levels of phospho-Smad1/5 and Id (inhibitor of DNA binding) gene expression in the monocrotaline model. In contrast, we observed increased TGF-β activity, again more marked in the monocrotaline model, as evidenced by increased phospho-Smad2/3 and increased expression of TGF-β–regulated genes. Immunohistochemistry revealed increased TGF-β 1 expression in pulmonary artery smooth muscle cells and macrophages surrounding remodeled pulmonary arteries in monocrotaline rats. Inhibition of activin receptor-like kinase-5 signaling in vivo with the selective small-molecule inhibitor IN-1233 prevented PAH, right ventricular hypertrophy, and vascular remodeling after monocrotaline injection and inhibited the progression of established PAH in this model. No significant effect was observed in hypoxic PAH. In vitro studies confirmed that TGF-β stimulated migration of distal rat pulmonary artery smooth muscle cells and that this effect was inhibited by IN-1233. Conclusions— Disruption of BMP/TGF-β signaling is more pronounced in the monocrotaline model of PAH than in the chronic hypoxia model. Increased TGF-β activity is associated with greater macrophage recruitment with monocrotaline treatment. Inhibition of TGF-β signaling via activin receptor-like kinase-5 prevents development and progression of PAH in the monocrotaline model and may involve inhibition of pulmonary artery smooth muscle cell migration.
Extracorporeal photopheresis affects interleukin (IL)-10 and IL-12 production by monocytes in patients with chronic graft-versus-host disease
Authors: M. Di Renzo, P. Rubegni, A.L. Pasqui, G. Pompella, G. De Aloe, P. Sbano, A. Cuccia, C. Castagnini, A. Auteri, F. Laghi Pasini, M. Fimiani
Journal: British Journal of Dermatology (2005)

Chronic graft-versus-host disease (cGVHD) is a major complication of allogeneic bone marrow transplantation. Extracorporeal photopheresis (ECP) has recently been introduced as an alternative treatment for cases of cGVHD refractory to conventional immunosuppressive treatment, but its mechanism of action is not yet clear.To investigate in seven patients with cGVHD the effects of ECP on resistance of monocytes to apoptosis and on monocyte cytokine production.We designed an in vitro model that could mimic the potential in vivo effect of reinfusion of peripheral blood mononuclear cells treated by ECP. The model was based on coculture of ECP-treated lymphocytes with untreated monocytes from the same patient.ECP did not accelerate spontaneous apoptosis of monocytes. However, ECP-treated monocytes produced increased amounts of interleukin (IL)-12. In contrast, IL-12 production by monocytes did not increase in cocultures, but IL-10 production was upregulated.These results suggest that reinfusion of large numbers of autologous apoptotic lymphocytes is significant for the therapeutic outcome of ECP through upregulation of IL-10, which is an immunosuppressive cytokine.
Transatlantic storm in a teacup
Authors: N. Duncan
Journal: BMJ (1996)

Earlier this month an American paper was published in the United Kingdom indicating a link between induced abortion and breast cancer. Conspiracy theorists emerged in force on both sides of the Atlantic, but the contrast between the way the British and American press reported the paper could hardly have been greater. While the British press, for the most part, reported the findings with a dispassionate calm, the American press indulged in a blitz of antiabortion conspiracy theories that would have bemused even Machiavelli.

It was this contrasting approach by the media in Britain and America that reportedly led the paper's author, Professor Joel Brind, to publish his research in a British journal which he assumed American medical reporters did not routinely read. So it was that …