tbuckley/cabot-search huggingface dataset:
Differential Diagnosis of Chronic Rheumatic Disease
Authors: H. W. Crowe
Journal: BMJ (1934)

The U.S. equity markets have dramatically evolved over the last decade. The evolution has been fueled by the rapid advance of technology, changes to market structure, increased competition among traditional and non-traditional market exchanges, changes in the regulatory framework, and a lack of coordinated oversight from regulators. Although trading in financial markets has changed substantially with the growth of new information processing and communications technologies, many of the issues centered on the fiduciary responsibility of providing best execution remain unchanged. Regulation and market structure have also changed. This article examines the current state of the U.S. equity markets. It explores how changes to market structure and regulation over the years have led us to where we are today and questions, <i>Is this really what we asked for</i>? <b>TOPICS:</b>Exchanges/markets/clearinghouses, financial crises and financial market history, equity portfolio management
P20 The eligibility of patients with difficult asthma for omalizumab since the change to the treatment criteria
Authors: A. Burton, B. Hargadon, A. Murphy, C. Brightling, I. Pavord, A. Wardlaw, P. Bradding, R. Green
Journal: Thorax (2010)

Omalizumab is a humanised monoclonal anti-IgE agent which is useful as an add-on therapy for severe atopic asthma. We have previously shown that 13.5% of patients attending our adult difficult asthma clinic were eligible for treatment with omalizumab. There has recently been a change to its prescribing licence with a widening of the eligible range of IgE from 30–700 iu/ml to 30–1500 iu/ml. Other prescribing criteria are (1) weight between 20 and 150 kg, (2) FEV<sub>1</sub> &lt;80% predicted, (3) positive skin prick tests or specific IgE to perennial aeroallergens and (4) ongoing symptoms despite a high-dose combination inhaler. In addition NICE guidance now recommends that its use is confined to patients who, within the past year, have had two or more hospital admissions or one admission plus two A&amp;E attendances for asthma exacerbations. We aimed to determine how the new licensing criteria and the NICE guidelines have affected the proportion of patients attending our difficult asthma clinic eligible for treatment with omalizumab. We assessed 510 patients recording body weight (kg), FEV<sub>1</sub> (% predicted), symptoms, total IgE (iU/ml) and skin prick tests. Our data demonstrate that 240 had an IgE outside the eligible range, 242 patients had an FEV<sub>1</sub>&gt;80%, 46 patients had negative skin prick tests and a further 2 patients′ weight was outside the range for dosing. 67/510 (13.1%) patients met all the licensing criteria for omalizumab. There has therefore not been any increase in the proportion of eligible patients since the widening of the IgE range. Of these 67, 27 patients had two or more admissions with asthma exacerbations in the previous year. A further 16 patients had one admission but less than 2 A&amp;E attendances. 12 patients required maintenance oral prednisolone but did not have sufficient admissions to meet the NICE prescribing guidelines. In total, 27/510 (5.3%) of patients with difficult-to-treat asthma were eligible for treatment with omalizumab according to NICE guidance. Although omalizumab is a helpful additional therapy for allergy-mediated asthma, its licensing criteria and current NICE guidelines limits its use in the UK to a small proportion of patients with difficult asthma.
A model of chronic lung allograft rejection in the rat
Authors: W. Jungraithmayr, P. Vogt, I. Inci, S. Hillinger, S. Arni, S. Korom, W. Weder
Journal: European Respiratory Journal (2009)

Bronchiolitis obliterans, the pathological hallmark of chronic pulmonary rejection, severely impacts long-term survival following lung transplantation. However, experimental reproduction of this pathophysiological phenomenon has not been achieved with contemporary in vivo models. Here, a model of chronic rejection is described, with sensitised recipients receiving unilateral orthotopic rat lung transplants. Lewis rats, sensitised with skin from brown Norway rats 7 days before receiving left lung transplants from donors that were Lewis×brown Norway F 1 hybrids, were analysed during day 21–84. The development of chronic rejection was modulated by a treatment with rapamycin and cyclosporin, and characterised histologically, immunohistochemically and by reverse transcriptase PCR. Characteristic histopathological changes leading to chronic rejection were induced over time by an initial treatment with cyclosporin in the presence of continuous rapamycin application. At day 84, fibrotic lesions replaced the respiratory epithelium within small bronchioles, with strong expression of smooth muscle α-actin and upregulation of mRNA for T-helper cell type-1 cytokines, smooth muscle α-actin, transforming growth factor-β and CC chemokine ligand 5, but decreased forkhead box protein P3 gene expression. A reproducible and clinically relevant experimental set-up for progressive chronic rejection in rat pulmonary allografts is described. This model will permit better understanding of the pathological changes of small airways during the development of bronchiolitis obliterans, and may serve as an in vivo set-up for testing the efficacy of novel therapeutic interventions.
The Soluble Wnt Receptor Frizzled8CRD-hFc Inhibits the Growth of Teratocarcinomas <i>In vivo</i>
Authors: Venita I. DeAlmeida, Li Miao, James A. Ernst, Hartmut Koeppen, Paul Polakis, Bonnee Rubinfeld
Journal: Cancer Research (2007)

Wnt signaling is important for normal cell proliferation and differentiation, and mutations in pathway components are associated with human cancers. Recent studies suggest that altered wnt ligand/receptor interactions might also contribute to human tumorigenesis. Therefore, agents that antagonize wnt signaling at the extracellular level would be attractive therapeutics for these cancers. We have generated a soluble wnt receptor comprising the Frizzled8 cysteine-rich domain (CRD) fused to the human Fc domain (F8CRDhFc) that exhibits favorable pharmacologic properties in vivo. Potent antitumor efficacy was shown using the mouse mammary tumor virus-Wnt1 tumor model under dosing conditions that did not produce detectable toxicity in regenerating tissue compartments. In vitro, F8CRDhFc inhibited autocrine wnt signaling in the teratoma cell lines PA-1, NTera-2, Tera-2, and NCCIT. In vivo, systemic administration of F8CRDhFc significantly retarded the growth of tumor xenografts derived from two of these cell lines, PA-1 and NTera-2. Pharmacodynamic markers of wnt signaling, identified by gene expression analysis of cultured teratoma cells, were also modulated in the tumor xenografts following treatment with F8CRDhFc. Additionally, these markers could be used as indicators of treatment efficacy and might also be useful in identifying patients that would benefit from the therapeutic agent. This is the first report showing the efficacy of a soluble wnt receptor as an antitumor agent and suggests that further development of wnt antagonists will have utility in treating human cancer.
A Genome-Wide Search for Promoters That Respond to Increased MYCN Reveals Both New Oncogenic and Tumor Suppressor MicroRNAs Associated with Aggressive Neuroblastoma
Authors: Jason M. Shohet, Rajib Ghosh, Cristian Coarfa, Andrew Ludwig, Ashley L. Benham, Zaowen Chen, Danielle M. Patterson, Eveline Barbieri, Pieter Mestdagh, Denae N. Sikorski, Aleksandar Milosavljevic, Eugene S. Kim, Preethi H. Gunaratne
Journal: Cancer Research (2011)

MYCN is a major driver of neuroblastoma tumorigenesis and MYCN amplification is the worst prognostic indicator of aggressive NB. To identify potentially therapeutic tumor suppressor microRNAs for aggressive NB, we utilized a conditional MYCN system to simulate MYCN-amplified and nonamplified tumor types and performed a genome-wide search for MYCN target microRNA promoters differentially repressed under high MYCN conditions. We identified 20 gene promoters hosting 30 microRNAs that were directly bound and differentially regulated by MYCN. Eleven of these genes showed significant clinical correlations for neuroblastoma with 4 genes linked with better survival and 7 genes linked with poor survival. Surprisingly, expression analysis of host genes and microRNAs demonstrated that 8 of 11 pairs were repressed by high levels of MYCN regardless of the clinical correlation of the host gene. We therefore predicted these intronic microRNAs would be tumor suppressors. In fact, detailed gain of function studies for two miRs, miR-591 and miR-558, confirmed potent tumor suppressive effects for miR-591 in orthotopic neuroblastoma xenografts. However, miR-558 markedly increased colony formation, proliferation, and tumor growth in vivo. Our data reveal host-gene independent functions of MYCN-target microRNAs and demonstrate that MYCN represses both tumor suppressive and proproliferative microRNAs.
Immuno-suppressive lymphocyte factors. I. Purification of inhibitor of DNA synthesis to homogeneity.
Authors: B V Jegasothy, D R Battles
Journal: The Journal of Experimental Medicine (1979)

Inhibitor of DNA synthesis (IDS) is a T-lymphocyte factor, whose role in immunnoregulation might be to nonspecifically suppress the immune system especially in situations where very high, prolonged tolerogenic doses of antigens are present. We have purified IDS-contained supernates of stimulated lymphocytes to homogeneity, through isoelectric focusing and Sephadex gel chromatography. IDS has an isoelectric point of 2.73-2.75 and in its monomeric form has a mol wt of 20,000 but exists in the supernate usually as an aggregated tetrameric form. Di- and trimeric forms are also seen. All forms are biologically active. Purity was confirmed by SDS gel electrophoresis and the binding of dansyl chloride to terminal or free amino groups of proteins and peptides. We have, further confirmed that pure IDS is not cytotoxic and is probably a glycoprotein whose activity depends on an intact carbohydrate moiety.
Suppression of elevations in serum C reactive protein levels by anti-IL-6 autoantibodies in two patients with severe bacterial infections
Authors: Toshihiro Nanki, Ikumi Onoue, Kenji Nagasaka, Aiko Takayasu, Masashi Ebisawa, Tadashi Hosoya, Toshizumi Shirai, Takahiko Sugihara, Shinya Hirata, Tetsuo Kubota, Masayoshi Harigai, Nobuyuki Miyasaka
Journal: Annals of the Rheumatic Diseases (2013)

Serum C reactive protein (CRP) is generally elevated by infection. We encountered two patients with severe bacterial infections without increases in CRP. Patient 1: A 67-year-old man developed thoracic empyema by Escherichia coli and Streptococcus intermedius . His body temperature was 36.6°C, his leukocyte count was elevated (9960/μl) and he was negative for CRP (0.01 mg/dl). Despite antibiotic treatment, he died of respiratory failure. Patient 2: A 56-year-old woman developed multiple subcutaneous abscesses by Staphylococcus aureus . She had rheumatoid arthritis (RA) for 30 years and was treated with sodium aurothiomalate. Her body temperature was 37.4°C, and leukocyte count (5600/μl) and CRP (0.05 mg/dl) were not elevated. She recovered with antibiotics. Neither patient had a past history of severe bacterial infection.

Since serum CRP is mainly controlled by interleukin (IL)-6,1 the lack of IL-6 function was suggested. Serum IL-6 was not detected by ELISA in either patient, although it is known to increase with severe infection.2 ,3 However, IL-6 production from peripheral blood monocytes with/without lipopolysaccharide stimulation was similar between Patient 1 and healthy controls (data not shown). Soluble IL-6 receptor (IL-6R) and IL-6 signal transducer (IL-6ST) serum levels were also …
Does the Search for Large Genomic Rearrangements Impact BRCAPRO Carrier Prediction?
Authors: Carlo Capalbo, Amelia Buffone, Annarita Vestri, Enrico Ricevuto, Christian Rinaldi, Massimo Zani, Sergio Ferraro, Luigi Frati, Isabella Screpanti, Alberto Gulino, Giuseppe Giannini
Journal: Journal of Clinical Oncology (2007)
Bronchodilator reversibility in COPD: the roguish but harmless little brother of airway hyperresponsiveness?
Authors: E. F. Hansen, J. Vestbo
Journal: European Respiratory Journal (2005)

Airway hyperresponsiveness (AHR) in chronic obstructive pulmonary disease (COPD) is well described in an epidemiological context with rather consistent results. It is known that AHR is a negative prognostic marker, associated with an accelerated decline in forced expiratory volume in one second (FEV1) 1–3 and probably also associated with an increase in mortality 4. The presence of AHR in individual subjects is almost constant. Thus, in the Lung Health Study (LHS), where responsiveness to methacholine was measured at two time points 5-yrs apart, <17% of the participants changed responsiveness by ≥2 concentrations 5. Smoking cessation is reported to have a beneficial effect on AHR 5, and smokers with high levels of AHR seem to gain more from smoking cessation in terms of FEV1 6.

Even if a lot of the “hows” for AHR in COPD are known, the “whys” have still not been answered. It is not known if AHR truly denotes a susceptibility to smoking, in line with the Dutch hypothesis, or if it is a mere reflection of the progression in COPD. AHR is, unlike in the case of asthma, resistant to current treatments, and extremely little is known of the underlying airway biology associated with AHR in COPD.

Bronchodilator reversibility (BDR) in COPD has also been extensively studied, but with more complex and confusing results than …
A Rare Case of Primary Cardiac Lymphoma Presented as Superior Vena Cava Syndrome
Authors: Nikolaos Koumallos, Charalambos Antoniades, Alexios S. Antonopoulos, Dimitris Tousoulis, Aristides Androulakis, Themistoklis Psarros, Christodoulos Stefanadis
Journal: Journal of the American College of Cardiology (2009)
Sexuality in Adult Cancer Survivors: Challenges and Intervention
Authors: Sharon L. Bober, Veronica Sanchez Varela
Journal: Journal of Clinical Oncology (2012)

Sexual dysfunction is one of the most common and distressing consequences of cancer treatment. Although some treatment-related sexual adverse effects are short-term, many survivors face long-term effects such as treatment-induced menopause, altered gonadal function, and significant surgical disfigurement. Profound sexual dysfunction has been shown to have a significant negative effect on quality of life. Although these problems have been well documented and there are a range of intervention strategies that can help patients cope with treatment-related sexual problems, many survivors do not feel prepared for potential sexual changes and often do not receive adequate support to manage sexual dysfunction. Numerous barriers contribute to this underprovided aspect of survivorship care, including lack of provider training and access to readily available resources. In addition, psychological, relational, and cultural factors significantly influence sexuality but are often not taken into consideration in research and clinical practice. By taking an integrative approach and providing survivors with appropriate screening, information, and support, sexual dysfunction and accompanying distress can be significantly alleviated. In this article, we aim to provide a concise review of the most common sexual problems experienced by survivors and highlight some of the most promising evidence-based practices for assessment and intervention. We also address limitations encountered in research and practice and explore future directions, including suggestions for adopting an integrative treatment model to address sexual dysfunction in a cancer survivorship treatment setting.
EGFR in colorectal cancer: more than a simple receptor
Authors: M. Francoual, M.-C. Etienne-Grimaldi, J.-L. Formento, D. Benchimol, A. Bourgeon, M. Chazal, C. Letoublon, T. André, N. Gilly, J.-R. Delpero, P. Lasser, J.-P. Spano, G. Milano
Journal: Annals of Oncology (2006)
Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use
Authors: Susanna M Proudman, Michael J James, Llewellyn D Spargo, Robert G Metcalf, Thomas R Sullivan, Maureen Rischmueller, Katerina Flabouris, Mihir D Wechalekar, Anita T Lee, Leslie G Cleland
Journal: Annals of the Rheumatic Diseases (2013)

Background The effects of fish oil (FO) in rheumatoid arthritis (RA) have not been examined in the context of contemporary treatment of early RA. This study examined the effects of high versus low dose FO in early RA employing a ‘treat-to-target’ protocol of combination disease-modifying anti-rheumatic drugs (DMARDs). Methods Patients with RA &lt;12 months’ duration and who were DMARD-naïve were enrolled and randomised 2:1 to FO at a high dose or low dose (for masking). These groups, designated FO and control, were given 5.5 or 0.4 g/day, respectively, of the omega-3 fats, eicosapentaenoic acid + docosahexaenoic acid. All patients received methotrexate (MTX), sulphasalazine and hydroxychloroquine, and DMARD doses were adjusted according to an algorithm taking disease activity and toxicity into account. DAS28-erythrocyte sedimentation rate, modified Health Assessment Questionnaire (mHAQ) and remission were assessed three monthly. The primary outcome measure was failure of triple DMARD therapy. Results In the FO group, failure of triple DMARD therapy was lower (HR=0.28 (95% CI 0.12 to 0.63; p=0.002) unadjusted and 0.24 (95% CI 0.10 to 0.54; p=0.0006) following adjustment for smoking history, shared epitope and baseline anti–cyclic citrullinated peptide. The rate of first American College of Rheumatology (ACR) remission was significantly greater in the FO compared with the control group (HRs=2.17 (95% CI 1.07 to 4.42; p=0.03) unadjusted and 2.09 (95% CI 1.02 to 4.30; p=0.04) adjusted). There were no differences between groups in MTX dose, DAS28 or mHAQ scores, or adverse events. Conclusions FO was associated with benefits additional to those achieved by combination ‘treat-to-target’ DMARDs with similar MTX use. These included reduced triple DMARD failure and a higher rate of ACR remission.
Association of <i>WNK1</i> Gene Polymorphisms and Haplotypes With Ambulatory Blood Pressure in the General Population
Authors: Martin D. Tobin, Stuart M. Raleigh, Stephen Newhouse, Peter Braund, Clare Bodycote, Jenny Ogleby, Deborah Cross, Jay Gracey, Saija Hayes, Terry Smith, Cathy Ridge, Mark Caulfield, Nuala A. Sheehan, Patricia B. Munroe, Paul R. Burton, Nilesh J. Samani
Journal: Circulation (2005)

Blood pressure (BP) is a heritable trait of major public health concern. The WNK1 and WNK4 genes, which encode proteins in the WNK family of serine-threonine kinases, are involved in renal electrolyte homeostasis. Mutations in the WNK1 and WNK4 genes cause a rare monogenic hypertensive syndrome, pseudohypoaldosteronism type II. We investigated whether polymorphisms in these WNK genes influence BP in the general population.Associations between 9 single-nucleotide polymorphisms (SNPs) in WNK1 and 1 in WNK4 with ambulatory BP were studied in a population-based sample of 996 subjects from 250 white European families. The heritability estimates of mean 24-hour systolic BP (SBP) and diastolic BP (DBP) were 63.4% and 67.9%, respectively. We found statistically significant (P<0.05) associations of several common SNPs and haplotypes in WNK1 with mean 24-hour SBP and/or DBP. The minor allele (C) of rs880054, with a frequency of 44%, reduced mean 24-hour SBP and DBP by 1.37 (95% confidence interval, -2.45 to -0.23) and 1.14 (95% confidence interval, -1.93 to -0.38) mm Hg, respectively, per copy of the allele.Common variants in WNK1 contribute to BP variation in the general population. This study shows that a gene causing a rare monogenic form of hypertension also plays a significant role in BP regulation in the general population. The findings provide a basis to identify functional variants of WNK1, elucidate any interactions of these variants with dietary intake or with response to antihypertensive drugs, and determine their impact on cardiovascular morbidity and mortality.
Long-Term Prediction of Prostate Cancer: Prostate-Specific Antigen (PSA) Velocity Is Predictive but Does Not Improve the Predictive Accuracy of a Single PSA Measurement 15 Years or More Before Cancer Diagnosis in a Large, Representative, Unscreened Population
Authors: David Ulmert, Angel M. Serio, Matthew F. O'Brien, Charlotte Becker, James A. Eastham, Peter T. Scardino, Thomas Björk, Göran Berglund, Andrew J. Vickers, Hans Lilja
Journal: Journal of Clinical Oncology (2008)

Purpose We tested whether total prostate-specific antigen velocity (tPSAv) improves accuracy of a model using PSA level to predict long-term risk of prostate cancer diagnosis. Methods During 1974 to 1986 in a preventive medicine study in Sweden, 5,722 men aged ≤ 50 gave two blood samples about 6 years apart. We measured free (fPSA) and total PSA (tPSA) in archived plasma samples from 4,907 participants. Prostate cancer was subsequently diagnosed in 443 (9%) men. Cox proportional hazards regression was used to evaluate tPSA and tPSAv as predictors of prostate cancer. Predictive accuracy was assessed by the concordance index. Results The median time from second blood draw to cancer diagnosis was 16 years; median follow-up for men without prostate cancer was 21 years. In univariate models, tPSA level at second assessment and tPSAv between first and second assessments were associated with prostate cancer (both P &lt; .001). tPSAv was highly correlated with tPSA level (r = 0.93). Twenty-year probabilities of cancer for men at 50th, 90th, and 95th percentile of tPSA and tPSAv were 10.6%, 17.1%, and 21.2% for tPSA, and 9.1%, 11.8%, and 14.1% for tPSAv, respectively. The concordance index for tPSA level was 0.771. Adding tPSAv, fPSA, %fPSA or velocities of fPSA and %fPSA did not importantly increase accuracy of tPSA to predict prostate cancer. Results were unchanged if the analysis was restricted to patients with advanced cancer at diagnosis. Conclusion Although PSA velocity is significantly increased in men with prostate cancer up to two decades before diagnosis, it does not aid long-term prediction of prostate cancer.
Inhibitory Effect of Angiotensin II Type 2 Receptor on Coronary Arterial Remodeling After Aortic Banding in Mice
Authors: Masahiro Akishita, Masaru Iwai, Lan Wu, Lunan Zhang, Yasuyoshi Ouchi, Victor J. Dzau, Masatsugu Horiuchi
Journal: Circulation (2000)

The renin-angiotensin system is thought to be critical for the development of cardiac hypertrophy, whereas the role of the angiotensin II type 2 (AT(2)) receptor in the process is not defined. Using the AT(2) receptor-null (Agtr2-) mouse, we tested the hypothesis that the AT(2) receptor could exert an antigrowth effect in cardiac hypertrophy.Cardiac hypertrophy was induced by suprarenal abdominal aortic banding in 10- to 12-week-old Agtr2- and wild-type (Agtr2+) mice for 6 or 12 weeks. Carotid arterial pressure was not different between the strains, although aortic banding increased arterial pressure by approximately 40 mm Hg. Aortic banding increased the heart-weight/body-weight ratio and the cross-sectional area of cardiomyocytes by 15%, resulting in comparable cardiomyocyte hypertrophy in the 2 strains. In contrast, coronary arterial thickening and perivascular fibrosis, determined by the media/lumen-area ratio and the collagen/vessel-area ratio, respectively, were 50% greater in Agtr2- than in Agtr2+ mice after banding, whereas these parameters were similar in sham-operated mice. Radioligand binding studies using the whole heart and immunohistochemistry showed that AT(2) receptor expression was limited and localized in the coronary artery and perivascular region.These results suggest that the AT(2) receptor mediates an inhibitory effect on coronary arterial remodeling, such as medial hypertrophy and perivascular fibrosis in response to pressure overload, and an activation of the renin-angiotensin system.