tbuckley/cabot-search huggingface dataset:
Bone mineral density in patients with recently diagnosed, active rheumatoid arthritis
Authors: M Guler-Yuksel, J Bijsterbosch, Y P M Goekoop-Ruiterman, F C Breedveld, C F Allaart, J K de Vries-Bouwstra, B A C Dijkmans, W F Lems, H K Ronday, A J Peeters, J M de Jonge-Bok
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> Osteoporosis is a well-known extra-articular phenomenon in patients with uncontrolled, long-standing rheumatoid arthritis (RA). In the present study, the extent of osteoporosis and reduced bone mineral density (BMD) and the disease-related and demographic factors that are associated with osteoporosis and reduced BMD were examined in patients with recently diagnosed, active RA. <h3>Methods:</h3> BMD of the total hip and the lumbar spine was measured using dual-energy <i>x</i> ray absorptiometry in 381 patients with recently diagnosed active RA, who had never been treated with DMARDs or corticosteroids. Osteoporosis was defined as a T score ⩽−2.5 SD and reduced BMD as Z score ⩽−1 SD. Multivariate logistic regression analyses were performed to detect associations of osteoporosis and reduced BMD with disease activity, functional disability, joint damage (Sharp–van der Heijde score) and demographic factors. <h3>Results:</h3> Osteoporosis and reduced BMD were found in the spine and/or the hip in 11% and 25%, respectively, of the patients. Longer symptom duration and presence of rheumatoid factor (RF) were the only RA-specific markers for osteoporosis and reduced BMD. Further, postmenopausal status in women, a low body mass index, familial osteoporosis, and, remarkably, male gender, were independently associated with osteoporosis and reduced BMD. <h3>Conclusion:</h3> In patients with recently diagnosed active RA who had never been treated with DMARDs or corticosteroids, BMD seems to be well-preserved and predominantly related to demographic factors. Longer symptom duration and a positive RF, but not higher disease activity or more joint damage, were related to osteoporosis and reduced BMD.
Clinical leadership and clinical followership
Authors: Maryam Alfa-Wali
Journal: Journal of the Royal Society of Medicine (2011)

In response to Abbasi's editorial,1 we need situational clinical leadership. Leaders that rise to the occasion with managerial responsibility in the NHS. The relationship between doctors and managers depends on negotiation and effective communication about organizational goals. Clear reasoning behind clinical priorities and economical objectives would create the happy medium between the two. The growth of clinical leadership as well as clinical followership needs to be encouraged with openness and innovativeness, to universally benefit patient care.
Extracellular calcium sensing receptor in human pancreatic cells
Authors: G Z Rácz, Á Kittel, D Riccardi, R M Case, A C Elliott, G Varga
Journal: Gut (2002)

<b>Background and aims:</b> The extracellular calcium sensing receptor (CaR) plays a key role in the calcium homeostatic system and is therefore widely expressed in tissues involved in calcium metabolism. However, the CaR has also been identified in other tissues where its role is less clear. We have investigated the presence of the CaR in the human pancreas. <b>Methods:</b> Messenger RNA for the CaR was detected by reverse transcription-polymerase chain reaction and the protein was localised by immunostaining. CaR function was assayed in Capan-1 cells by measuring intracellular calcium and [<sup>3</sup>H] thymidine incorporation. <b>Results:</b> The receptor was highly expressed in human pancreatic ducts. It was also expressed in exocrine acinar cells, in islets of Langerhans, and in intrapancreatic nerves and blood vessels. The CaR was expressed in both normal and neoplastic human tissue samples but was detected in only one of five ductal adenocarcinoma cells lines examined. Experiments on the CaR expressing adenocarcinoma cell line Capan-1 showed that the CaR was functional and was linked to mobilisation of intracellular calcium. Stimulation of the CaR reduced Capan-1 cell proliferation. <b>Conclusions:</b> We propose that the CaR may play multiple functional roles in the human pancreas. In particular, the CaR on the duct luminal membrane may monitor and regulate the Ca<sup>2+</sup> concentration in pancreatic juice by triggering ductal electrolyte and fluid secretion. This could help to prevent precipitation of calcium salts in the duct lumen. The CaR may also help to regulate the proliferation of pancreatic ductal cells.
The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomised placebo-controlled trial
Authors: Clive Ballard, Maria Luisa Hanney, Megan Theodoulou, Simon Douglas, Rupert McShane, Katja Kossakowski, Randeep Gill, Edmund Juszczak, Ly-Mee Yu, Robin Jacoby
Journal: The Lancet Neurology (2009)
Enhanced prostanoid release from monocytes of patients with rheumatoid arthritis and active systemic lupus erythematosus.
Authors: M Seitz, W Hunstein
Journal: Annals of the Rheumatic Diseases (1985)

In patients with rheumatoid arthritis high levels of prostaglandin E1 have been found in the joint fluid, and its increased production by adherent synovial cells and macrophages clearly supports the notion that this arachidonic acid metabolite is involved in the pathology of the disease. Besides its known inflammatory qualities and the suppressive effects on various lymphocyte functions prostaglandin E2 has proved to be an essential cofactor in the secretion of the lymphokine osteoclast activating factor. In this study we have discovered an enhanced release of prostaglandin E1 and thromboxane B2 from a subpopulation of blood monocytes from patients with rheumatoid arthritis and active systemic lupus erythematosus. No correlation between prostanoid release from monocytes and inflammatory activity of the disease was found. However, even monocytes from patients with early stage or mild inflammatory activity displayed a 'stimulated' arachidonic acid metabolism. In contrast only patients with active systemic lupus erythematosus showed in this respect comparable secretory activity or monocytes. Our findings may point to a possible pathogenic role of prostanoids in rheumatoid arthritis, which may also have some implication for the early diagnosis of this disease and for its differentiation from other chronic inflammatory rheumatic conditions.
Postoperative neuralgia in the leg after saphenous vein coronary artery bypass graft: a prospective study.
Authors: U R Nair, G Griffiths, R A Lawson
Journal: Thorax (1988)

The degree of cutaneous sensory deficit in the leg was assessed after removal of the long saphenous vein in 50 consecutive patients undergoing coronary artery bypass vein grafts randomly assigned subcutaneous sutures or a single layer of sutures. Removal of the vein and repair of the leg incision were done by the same team of surgeons. In group 1 (25 patients) the leg incision was repaired with "00" Dexon subcutaneous and "00" prolene subcuticular sutures while in group 2 (25 patients) closure was effected by a single layer of interrupted "00" nylon sutures. All had crepe pressure bandage from the base of the toes to the groin for the first 24 hours followed by TED stockings for six to eight weeks. Sutures were removed on the eighth postoperative day. Cutaneous sensation in the leg and ankle was assessed 48 hours, seven days, and six to eight weeks after surgery, and a final comparison of the cosmetic effects and sensory perception after one year or more was made in 37 patients. There were no major differences between the groups at 48 hours in sensory abnormalities (anaesthesia, hyperaesthesia, and pain) but sensory recovery was significantly better in group 2 at the second and third assessments. There was some reduction in sensory abnormalities at the final review in group 1. No appreciable difference was noted in the quality of the scar between the two groups. We conclude that cutaneous sensation is better preserved by repairing the leg incision in a single layer. Subcutaneous sutures may produce neuropraxia of the long saphenous nerve by direct pressure as healing progresses.
Synergism between Arsenic Trioxide and Heat Shock Protein 90 Inhibitors on Signal Transducer and Activator of Transcription Protein 3 Activity—Pharmacodynamic Drug-Drug Interaction Modeling
Authors: Meir Wetzler, Justin C. Earp, Michael T. Brady, Michael K. Keng, William J. Jusko
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Constitutive signal transducer and activator of transcription 3 (STAT3) activity, observed in ∼50% of acute myelogenous leukemia cases and associated with adverse treatment outcome, is down-regulated by arsenic trioxide (ATO). Heat shock protein (HSP) 90 is a molecular chaperone involved in signal transduction pathways. We hypothesized that HSP90 inhibitors will potentiate ATO effect on constitutive STAT3 activity and cell killing. One concern was that the effect of ATO and HSP90 inhibitors will result in up-regulation of HSP70, a protein known to inhibit apoptosis. Experimental Design: We have used a semimechanistic pharmacodynamic model to characterize concentration-effect relationships of ATO and HSP90 inhibitors on constitutive STAT3 activity, HSP70 expression, and cell death in a cell line model. Results: Pharmacodynamic interaction of ATO and three HSP90 inhibitors showed synergistic interactions in inhibiting constitutive STAT3 activity and inducing cell death, in spite of a concurrent synergistic up-regulation of HSP70. Conclusions: These preliminary results provide a basis for studying the combined role of ATO with HSP90 inhibitors in acute myelogenous leukemia with constitutive STAT3 activity.
Modified mRNA encoding Foxp3 protects against allergic asthma in mice by rebalancing T helper cell responses through an IL-23 / IL-17A-dependent mechanism
Authors: Lauren Mays, Susanne Ammon-Treiber, Benedikt Mothes, Markus Mezger, Rupert Handgretinger, Dominik Hartl, Michael Kormann
Journal: European Respiratory Journal (2012)

Chemically modified mRNA has recently shown life-saving efficacy in a murine model of a rare, genetic lung disease, Surfactant Protein-B deficiency, by inducing therapeutic levels of protein expression while circumventing the threat of genomic integration often associated with viral vectors (Kormann et al, Nat Biotechnol. 2011 Feb; 29(2):154-7). To translate this novel therapeutic tool into a high prevalence disease model, we investigated whether modified mRNA could restore immune balance and alleviate disease severity in Th2-driven allergic asthma. We show that intratracheal delivery of modified mRNA coding for the regulatory T cell factor Foxp3 rebalanced pulmonary T helper cell responses, modulated innate immune cell recruitment, and protected from allergen-induced tissue inflammation and goblet cell metaplasia. Protection against asthma was achieved following delivery of modified mRNA either before or after the onset of allergen challenge, demonstrating its potential as both a preventative and a therapeutic. Mechanistically, Foxp3 upregulation was critical in downregulating IL-23 and IL-17 production, and recombinant IL-23 or IL-17 expression during challenge abolished protection conferred by Foxp3 mRNA. Taken together, our results provide evidence that chemically modified Foxp3 mRNA protects against allergic asthma in vivo, which may pave the way for considering modified mRNA as a safe therapeutic tool for the treatment of asthma, allergy and beyond.
Host type I IFN signals are required for antitumor CD8+ T cell responses through CD8α+ dendritic cells
Authors: Mercedes B. Fuertes, Aalok K. Kacha, Justin Kline, Seng-Ryong Woo, David M. Kranz, Kenneth M. Murphy, Thomas F. Gajewski
Journal: The Journal of Experimental Medicine (2011)

Despite lack of tumor control in many models, spontaneous T cell priming occurs frequently in response to a growing tumor. However, the innate immune mechanisms that promote natural antitumor T cell responses are undefined. In human metastatic melanoma, there was a correlation between a type I interferon (IFN) transcriptional profile and T cell markers in metastatic tumor tissue. In mice, IFN-β was produced by CD11c+ cells after tumor implantation, and tumor-induced T cell priming was defective in mice lacking IFN-α/βR or Stat1. IFN signaling was required in the hematopoietic compartment at the level of host antigen-presenting cells, and selectively for intratumoral accumulation of CD8α+ dendritic cells, which were demonstrated to be essential using Batf3−/− mice. Thus, host type I IFNs are critical for the innate immune recognition of a growing tumor through signaling on CD8α+ DCs.
Irreversibly sickled erythrocytes: a consequence of the heterogeneous distribution of hemoglobin types in sickle-cell anemia
Authors: John F. Bertles, Paul F. A. Milner
Journal: Journal of Clinical Investigation (1968)

THE AMOUNT OF FETAL HEMOGLOBIN (HB F) IN ERYTHROCYTES OF PATIENTS WITH SICKLE CELL ANEMIA (HB SS DISEASE) WAS MEASURED BY TWO METHODS: (a) photometry of individual cells stained for Hb F by the Kleihauer-Betke technique; and (b) chemical assay of alkali-resistant hemoglobin in cells distributed according to specific gravity by ultracentrifugation. Irreversibly sickled cells (ISC), which could be identified directly during photometry and which were found to gather in high concentration at the bottom of ultracentrifuged cell columns, contained significantly less Hb F than non-ISC. Cell content of total Hb was constant regardless of cell size, shape, or ultracentrifugal behavior: thus absolute amounts of Hb F and S varied reciprocally from cell to cell. In experiments designed to estimate age, at formation, and rate of destruction of ISC, Hb SS blood was incubated with selenomethionine-(75)Se (which labels reticulocytes) or (51)Cr (which labels erythrocytes at random) and reinfused. Sequential blood samples were separated by ultracentrifugation into fractions rich in reticulocytes, non-ISC, and ISC; and chronological changes in the specific activity of each fraction were determined. Analogous information was obtained from radioautography of sequential blood samples after reinfusion of whole blood labeled with amino acids-(3)H: this technique permitted direct visual characterization of labeled erythrocytes as ISC or non-ISC, all of which had been reticulocytes at the time of reinfusion. The transformation of non-ISC into ISC, presumably a manifestation of membrane damage, proved to begin soon after cell release from the marrow; and ISC subsequently underwent rapid removal from the circulating blood. IT IS THEREFORE APPARENT FROM THESE STUDIES THAT, IN HB SS DISEASE, RELATIVELY SMALL RECIPROCAL CHANGES IN THE AMOUNTS OF THE TWO MAJOR HEMOGLOBINS CARRY PREDICTIVE IMPORTANCE: (a) net synthesis of Hb F is least in erythroid cells destined to become ISC; and (b) these irreversibly deformed erythrocytes suffer preferential destruction.
Molecular Response to Cetuximab and Efficacy of Preoperative Cetuximab-Based Chemoradiation in Rectal Cancer
Authors: Annelies Debucquoy, Karin Haustermans, Anneleen Daemen, Selda Aydin, Louis Libbrecht, Olivier Gevaert, Bart De Moor, Sabine Tejpar, William H. McBride, Freddy Penninckx, Pierre Scalliet, Christopher Stroh, Soetkin Vlassak, Christine Sempoux, Jean-Pascal Machiels
Journal: Journal of Clinical Oncology (2009)

To characterize the molecular pathways activated or inhibited by cetuximab when combined with chemoradiotherapy (CRT) in rectal cancer and to identify molecular profiles and biomarkers that might improve patient selection for such treatments.Forty-one patients with rectal cancer (T3-4 and/or N+) received preoperative radiotherapy (1.8 Gy, 5 days/wk, 45 Gy) in combination with capecitabine and cetuximab (400 mg/m2 as initial dose 1 week before CRT followed by 250 mg/m2 /wk for 5 weeks). Biopsies and plasma samples were taken before treatment, after cetuximab but before CRT, and at the time of surgery. Proteomics and microarrays were used to monitor the molecular response to cetuximab and to identify profiles and biomarkers to predict treatment efficacy.Cetuximab on its own downregulated genes involved in proliferation and invasion and upregulated inflammatory gene expression, with 16 genes being significantly influenced in microarray analysis. The decrease in proliferation was confirmed by immunohistochemistry for Ki67 (P = .01) and was accompanied by an increase in transforming growth factor-alpha in plasma samples (P < .001). Disease-free survival (DFS) was better in patients if epidermal growth factor receptor expression was upregulated in the tumor after the initial cetuximab dose (P = .02) and when fibro-inflammatory changes were present in the surgical specimen (P = .03). Microarray and proteomic profiles were predictive of DFS.Our study showed that a single dose of cetuximab has a significant impact on the expression of genes involved in tumor proliferation and inflammation. We identified potential biomarkers that might predict response to cetuximab-based CRT.
Mental illness and the workplace: conceal or reveal?
Authors: Kay Wheat, Elaine Brohan, Claire Henderson, Graham Thornicroft
Journal: Journal of the Royal Society of Medicine (2010)

Doctors are frequently asked by patients whether they should disclose a mental illness when applying for work. Recognizing the potential for discrimination on the part of employers, many doctors advise concealment. However, concealment is attended by legal and psychological disadvantages. In this paper we discuss the pros and cons of disclosure and concealment that underlie this dilemma, and conclude that the current legal safeguards are unsatisfactory. We call for clarification of the law to support people with mental illness who wish to work, in the form of a specific amendment to the current Equality Bill.
ENHANCEMENT OF ANTIBIOTIC ACTIVITY OF COLICINE K AND ALTERATION OF SEROLOGICAL PROPERTIES OF COLICINE K AND ENDOTOXINS
Authors: Helen van Vunakis, Anna Ruffilli, Lawrence Levine
Journal: The Journal of Experimental Medicine (1965)

Hemoglobin, its chains, and myoglobin enhance the antibiotic activity of colicine K. These proteins also interact with colicine K and other O antigens to alter their serological activity. The hemoglobin proteins did not alter the serological activities of three Pneumococcus polysaccharides or T4 bacteriophage DNA antigens but did alter the antigenic activity of fetuin. Interaction of hemoglobin and colicine K resulted in a retardation of colicine K antibiotic moiety as measured by gel filtration but did not affect the gel filtration properties of the lipopolysaccharide moiety.
Disappearance of Humoral Thyroid Autoimmunity after Complete Removal of Thyroid Antigens
Authors: Luca Chiovato, Francesco Latrofa, Lewis E. Braverman, Furio Pacini, Marco Capezzone, Lucio Masserini, Lucia Grasso, Aldo Pinchera
Journal: Annals of Internal Medicine (2003)

The development of antibodies to thyroid peroxidase, thyroglobulin, and thyroid-stimulating hormone (TSH) receptor is a main feature of autoimmune thyroid diseases.To investigate whether complete removal of thyroid antigens results in the abatement of humoral thyroid autoimmunity.Retrospective chart review study of patients treated and monitored with a standard prospective protocol.University hospital in Pisa, Italy, between 1976 and 1994.182 patients with differentiated thyroid carcinoma and serum antibodies to thyroid peroxidase, thyroglobulin, or TSH receptor due to coexistent clinical Hashimoto thyroiditis, Graves disease, or focal autoimmune thyroiditis.Total thyroidectomy and radioiodine treatment to ablate residual or metastatic thyroid tissue. Regular follow-up with iodine-131 whole-body scanning and serum thyroglobulin measurement. Mean follow-up (+/-SD) was 10.1 +/- 4.1 years (range, 4 to 20 years).Serum antibodies to thyroid peroxidase, thyroglobulin, and TSH receptor.Thyroid peroxidase, thyroglobulin, and TSH-receptor antibodies progressively disappeared after the initial treatment. The median disappearance time was 6.3 years for thyroid peroxidase antibodies and 3.0 years for thyroglobulin antibodies. There was a statistically significant correlation between the disappearance of thyroid tissue and that of thyroid antibodies. The coexistence of Hashimoto thyroiditis or Graves disease with thyroid cancer did not modify the pattern of disappearance of thyroid antibody compared with patients with focal autoimmune thyroiditis.Complete ablation of thyroid tissue with its antigenic components results in the disappearance of antibodies to all major thyroid antigens, thus supporting the concept that continued antibody production depends on the persistence of autoantigen in the body.
MARROW TRANSPLANTATION FOR MYELOMA
Authors: J.P. Fermand, M.D, J.C. Brouet, M.D
Journal: Annual Review of Medicine (1995)

High-dose therapy with hemopoietic stem cell support in multiple myeloma (MM) has been used for 10 years. This approach is currently the most promising form of treatment for this disease. We review here its rationale and the results of clinical trials according to the source of hematopoietic stem cells [allogeneic or autologous, bone marrow or blood]. Finally, we discuss the ongoing uncertainties regarding the utility of this treatment and the future prospects for high-dose therapy in MM.
TREATMENT OF LUPUS ERYTHEMATOSUS WITH GOLD COMPOUNDS
Authors: J. H. T. Davies
Journal: BMJ (1929)

<h3>Abstract</h3> Triterpenoids, one of the most diverse classes of natural products, have been used for centuries as active ingredients in essential oils and Chinese medicines and are of interest for many industrial applications ranging from low-calorie sweeteners to cosmetic ingredients and vaccine adjuvants. However, not only can the extraction from plant material be cumbersome due to low concentrations of the specific triterpenoid, but concerns are also increasing regarding the sustainability of wild plant harvest while meeting market demands. The alternative is to produce triterpenoids with engineered microbes. Here, we present a generally applicable strategy for triterpenoid production in the yeast <i>Saccharomyces cerevisiae</i> based on a modified oxidosqualene cyclase Erg7. The modification reduces the flux into the sterol pathway while increasing the precursor supply for triterpenoid production. The minimally engineered strain was exploited for the exemplary production of the lupane triterpenoids betulin, betulin aldehyde, and betulinic acid at a total titer above 6 g/L, the highest reported so far. To further highlight the chassis concept, squalene, oleanane- and dammarane-type triterpenoids were synthesized to titers at a similar gram scale. We propose the developed baker’s yeast as a host for the thousands of triterpenoid synthesis pathways from plants, reducing the pressure on the natural resources.