tbuckley/cabot-search huggingface dataset:
OC-018 Limited long Term Tolerance of Methotrexate For Inflammatory Bowel Disease: 11 Years Experience from a Single Centre
Authors: A J Brooks, E M Wood, K Robinson, A Wright, M E McAlindon, A J Lobo
Journal: Gut (2013)

<h3>Introduction</h3> Methotrexate (MTX) is used as an immunosuppressive treatment in inflammatory bowel disease (IBD). The aim of the study was to evaluate the long-term tolerability of MTX in adults with IBD from a large, single, tertiary referral centre. <h3>Methods</h3> IBD patients who had received MTX at a single centre between 2000 – 2011 were identified from the IBD service database and clinical records reviewed. <h3>Results</h3> 137 patients received MTX (Crohn’s Disease 105 (77%); ulcerative colitis (UC) 32 (23%)); mean age 44 (range 18–77). The median duration of MTX treatment was 13 months (range 1–127) with an initial dose of 25mg/week (range 10–25 mg) in 127/137 (93%) with 94% commencing MTX intramuscularly. The proportion who continued MTX for ≥ 3, 5, 10 years were 24% (33/137), 10% (14/137) and 1.5% (2/137) respectively. 89/137 (65%) discontinued MTX during the 11 year follow-up. The cessation rate due to lack of effectiveness was 17/137 (12%) by the end of the 2<sup>nd</sup> year of MTX, after which there were no further discontinuations for this reason. 77/137 (57%) reported ≥ 1 side-effect (SE) attributed to MTX, which was the commonest reason for discontinuing MTX (61/89; 69%). SEs leading to MTX cessation were most frequent during induction (defined as 0–3months): 22/61 (36%); followed by 3–12 months following initiation of MTX: 16/61 (26%). Specific SEs resulting in cessation during the 1st year of MTX were due to ≥ 1 of the following; 15 (40%) gastrointestinal (GI), 12 (32%) neurological (NS), 5 (13%) nonspecific malaise, 5 (13%) abnormal hepatic aminotransferase levels (2-fold increase up to or over the upper limit of normal), 2 (5%) hair loss, 5 other (1 each of sore throat, rash, infection, low platelets, injection site reaction). The incidence of discontinuation due to SEs in successive MTX years fell from commencement of MTX: 10/61 (16%) in the 2<sup>nd</sup> year, 5/61 (8%) in the 3<sup>rd</sup> year, 3/61 (5%) in the 4<sup>th</sup> year and 5 (8%) in total between the 5<sup>th</sup>-10<sup>th</sup> years. The most frequent SEs attributed to late discontinuation ( &gt; 1year) were GI and NS. Over 11 years there were 12/137 (9%) reported cases of presumed MTX induced abnormal hepatic aminotransferase levels, of which 8 (67%) resulted in MTX cessation with biochemical resolution. Hepatotoxicity occurred during induction in 7/12 cases (58%) and was stopped in 5 of these (71%). In 5 patients with late abnormal hepatic aminotransferase levels, the median time to detection was 36 months (range 10–100months). MTX was discontinued in 3 of these. <h3>Conclusion</h3> In the largest single-centre experience to date, MTX in IBD is limited by high withdrawal rates with a 28% discontinuation rate due to SEs within the 1st year. Late hepatoxicity highlights the need for long term monitoring in maintenance therapy. <h3>Disclosure of Interest</h3> None Declared
Mechanism of Action of Colchicine in Acute Urate Crystal-Induced Arthritis
Authors: Isaias Spilberg, Brian Mandell, Jagdish Mehta, Louis Simchowitz, David Rosenberg
Journal: Journal of Clinical Investigation (1979)

Phagocytosis of urate crystals by human or rabbit neutrophils induces the synthesis and release of a glycoprotein, the crystal-induced chemotactic factor (CCF), which is chemotactically active both in vitro and in vivo. It has been proposed that CCF is a prime mediator of the acute gouty attack. Colchicine has been shown to decrease the production and release of this factor in vitro. In these studies, colchicine, at nonleukopenic doses, is shown to abrogate the acute arthritis induced by monosodium urate crystals in rabbits, but to have no effect upon the arthritis induced by the injection of the purified cell-derived chemotactic factor. Serum colchicine levels were 0.48-0.58 μM at 30 min and 0.12-0.3 μM at 90 min after intravenous injection of 0.2 mg/kg colchicine. Peripheral blood polymorphonuclear leukocytes obtained from colchicine-treated animals migrated normally towards a chemotactic stimulus but failed to produce CCF after phagocytosis of monosodium urate crystals. The dialyzed synovial fluid from rabbits injected with microcrystalline sodium urate contained chemotactic activity that was not present when animals were also given intravenous colchicine or injected intra-articularly with the chemotactic factor formyl-methionyl-leucyl-phenylalanine. Furthermore, the synovial fluid from rabbits injected with microcrystalline sodium urate significantly decreased 125I-CCF binding to neutrophils. The binding of 125I-CCF to its neutrophil receptor was not significantly reduced by the synovial fluid of colchicine-treated rabbits nor by the synovial fluid of control rabbits injected with the chemotactic factor formyl-methionyl-leucyl-phenylalanine. Colchicine (10 and 0.1 μM) was shown to have no effect upon the binding of 125I-CCF to its cell receptor.
Anti-tumor effects of fibroblast growth factor-binding protein (FGF-BP) knockdown in colon carcinoma
Authors: Daniel Schulze, Philipp Plohmann, Sabrina Höbel, Achim Aigner
Journal: Molecular Cancer (2011)

Abstract Background Fibroblast growth factors FGF-1 and FGF-2 are often upregulated in tumors, but tightly bound to heparan sulphate proteoglycans of the extracellular matrix (ECM). One mechanism of their bioactivation relies on the FGF-binding protein (FGF-BP) which, upon reversible binding to FGF-1 or -2, leads to their release from the ECM. FGF-BP increases tumorigenicity and is highly expressed in tumors like colon carcinoma. In this paper, we analyse cellular and molecular consequences of RNAi-mediated FGF-BP knockdown in colon carcinoma, and explore the therapeutic effects of the nanoparticle-mediated delivery of small interfering RNAs (siRNAs) for FGF-BP targeting. Results Employing stable RNAi cells, we establish a dose-dependence of cell proliferation on FGF-BP expression levels. Decreased proliferation is mirrored by alterations in cell cycle distribution and upregulation of p21, which is relevant for mediating FGF-BP effects. While inhibition of proliferation is mainly associated with reduced Akt and increased GSK3β activation, antibody array-based analyses also reveal other alterations in MAPK signalling. Additionally, we demonstrate induction of apoptosis, mediated through caspase-3/7 activation, and alterations in redox status upon FGF-BP knockdown. These effects are based on the upregulation of Bad, Bax and HIF-1α, and the downregulation of catalase. In a therapeutic FGF-BP knockdown approach based on RNAi, we employ polymer-based nanoparticles for the in vivo delivery of siRNAs into established wildtype colon carcinoma xenografts. We show that the systemic treatment of mice leads to the inhibition of tumor growth based on FGF-BP knockdown. Conclusions FGF-BP is integrated in a complex network of cytoprotective effects, and represents a promising therapeutic target for RNAi-based knockdown approaches.
Survival Benefit of Breast Surgery for Low-Grade Ductal Carcinoma In Situ
Authors: Yasuaki Sagara, Melissa Anne Mallory, Stephanie Wong, Fatih Aydogan, Stephen DeSantis, William T. Barry, Mehra Golshan
Journal: JAMA Surgery (2015)

IMPORTANCE While the prevalence of ductal carcinoma in situ (DCIS) of the breast has increased substantially following the introduction of breast-screening methods, the clinical significance of early detection and treatment for DCIS remains unclear.OBJECTIVE To investigate the survival benefit of breast surgery for low-grade DCIS.
Age and Adjuvant Chemotherapy Use After Surgery for Stage III Colon Cancer
Authors: D. Schrag, L. D. Cramer, P. B. Bach, C. B. Begg
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Randomized trials have established that 5-fluorouracil-based adjuvant chemotherapy following resection of stage III colon cancer reduces subsequent mortality by as much as 30%. However, the extent to which adjuvant therapy is used outside the clinical trial setting, particularly among the elderly, is unknown. Methods: A retrospective cohort study utilizing the Surveillance, Epidemiology, and End Results/Medicare-linked database identified 6262 patients aged 65 years and older with resected stage III colon cancer. The primary outcome was chemotherapy use within 3 months of surgery, as ascertained from Medicare claims. We examined the extent to which age at diagnosis was associated with adjuvant chemotherapy usage, and we adjusted for potential confounding based on differences in other patient characteristics with the use of multiple logistic regression. All P values were two-sided. Results: Age at diagnosis was the strongest determinant of chemotherapy: 78% of patients aged 65–69 years, 74% of those aged 70–74 years, 58% of those aged 75–79 years, 34% of those aged 80–84 years, and 11% of those aged 85–89 years received postoperative chemotherapy. The age trend remained pronounced after adjustment for potential confounding based on variation in patients' demographic and clinical characteristics and after exclusion of patients with any evident comorbidity (all P values <.001). Conclusions: Adjuvant chemotherapy for stage III colon cancer is used extensively, especially for patients under the age of 75 years. However, treatment rates decline dramatically with chronologic age. Because patients in their 70s and even 80s have a reasonable life expectancy, further efforts are needed to ensure that elderly patients have the opportunity to make informed decisions regarding this potentially curative treatment.
IL-6 and TNF-α Synergistically Inhibit Allograft Acceptance
Authors: Hua Shen, Daniel R. Goldstein
Journal: Journal of the American Society of Nephrology (2009)

Previous studies suggested that activation of the innate immune system impairs the induction of transplantation tolerance, but the responsible inflammatory mediators have not been identified. In this study, we examined whether IL-6 and TNF-α promote resistance to transplantation tolerance. Using a highly immunogenic murine skin allograft model, we found that the absence of both IL-6 and TNF-α in the graft recipient synergized with co-stimulatory blockade to induce tolerance. Furthermore, IL-6 and TNF-α acted together to promote T cell alloimmune responses both in vitro and in vivo and to impair the ability of regulatory T cells to suppress effector T cell alloimmunity. In addition, deficiency of recipient IRAK-M, a negative regulator of certain innate immune pathways, augmented cellular IL-6 and TNF-α responses and impaired the ability of co-stimulatory blockade to extend allograft survival. In summary, IL-6 and TNF-α synergistically impair the efficacy of therapies that promote allograft acceptance.
Current Processes of the U.S. Preventive Services Task Force: Refining Evidence-Based Recommendation Development
Authors: Janelle Guirguis-Blake, Ned Calonge, Therese Miller, Albert Siu, Steven Teutsch, Evelyn Whitlock
Journal: Annals of Internal Medicine (2007)

The U.S. Preventive Services Task Force (USPSTF), an independent panel that has provided the gold standard for evidence-based guidelines in prevention for the past 2 decades, continuously refines its methodology. To keep up with the evolving field of evidence- based medicine and to update recommendations in a timely, efficient, and transparent manner, the USPSTF has developed new methods for evidence reviews and recommendation development. This article summarizes the most recent changes in the recommendation development process, including how the USPSTF solicits and prioritizes topics for review, updates evidence reviews and recommendations, and communicates with its audience.
Ionized calcium in normal serum, ultrafiltrates, and whole blood determined by ion-exchange electrodes
Authors: Edward W. Moore
Journal: Journal of Clinical Investigation (1970)

A B S T R A C T Ion-exchange calcium electrodes repre- sent the first practical method for the direct measurement of ionized calcium [Ca"+] in biologic fluids.Using both "static" and "flow-through" electrodes, serum [Ca"+] was within a rather narrow range: 0.94-1.33mmoles/ liter (mean, 1.14 mmoles/liter).Within a given indi- vidual, [Ca"+] varied only about 6%/C over a several month p)eriod.Consistent pH effects on [Ca++] were ob- served in serum and whole blood, [Ca++] varying inversely wvith pH.Less consistent pH effects were also noted in ultrafiltrates, believed to largely represent precipitation of certain calcium complexes from a supersaturated solu- tion.Heparinized whole blood [Ca++] was significantly less than in corresponding serum at normal blood pH, related to the formation of a calcium-heparin complex.[Ca++] in ultrafiltrates represented a variable fraction (66.7-90.2,) of total diffusible calcium.There was no apparent correlation between serum ionized and total calcium concentrations.Thus, neither serum total cal- cium nor total ultrafiltrable calcium provided a reliable index of serum [Ca++].Change in serum total calcium was almost totally accounted for by corresponding change in protein-bound calcium rCaProt].About 81% of [CaProt] was estimated to be bound to albumin and about 19%7 to globulins.From observed pH.serum pro- tein, and [CaProt] data, a nomogram was developed for estimating rCaProt] without ultrafiltration.Data pre- sented elsewhere indicate that calcium binding by serum proteins obeys the mass-law equation for a monoligand association.This was indicated in the present studies by a close correspondence of observed serum [Ca++I values with those predicted by the McLean-Hastings nomogram.These studies were included as part of a symposium, January 1969 (1) and preliminary reports have appeared previously (2, 3).
The mechanism of positive inotropy induced by adenosine triphosphate in rat heart.
Authors: F Scamps, A Legssyer, E Mayoux, G Vassort
Journal: Circulation Research (1990)

When applied extracellularly in the micromolar range, ATP and related compounds induced a positive inotropy in the rat papillary muscle. This was also true in the rat auricle after pertussis toxin treatment. Then, in both tissues, ATP further increased the contraction after a maximal beta-adrenergic stimulation. The increase in contractile force could be related to the increase in the calcium current. The L-type calcium current was measured by whole-cell patch-clamp recording in single cells isolated from the rat ventricle after the sodium and potassium currents were inhibited by tetrodotoxin and cesium, respectively. When added alone, 10 microM ATP increased the calcium current by 60%. Adenosine 5'-O-(3-thiotriphosphate) was also able to increase calcium current. Adenosine was much less effective, and GTP, UTP, CTP, and ITP were without effect. A similar increase in calcium current was observed when ATP was added in addition to a maximal stimulation by a beta-adrenergic agonist or after internal perfusion with cyclic AMP. However, this increase was preceded by a transient decrease whose origin could not be attributed to a P1-purinergic agonistic effect of ATP. The transient decrease was not elicited by adenosine or in a magnesium-free HEPES solution and was not suppressed after pertussis toxin treatment. This effect appeared related to the variations in the holding current also observed upon ATP application. Together with vasodilation, ATP and adenine compounds induced positive inotropy. The latter effect could be attributed in part to the increase in calcium current and was independent of cyclic AMP. Both effects are complementary with the beta-adrenergic stimulation and can help healthy cells to compensate the failing zone from which ATP could be released.
Multiple independent evolutionary solutions to core histone gene regulation.
Authors: Leonardo Mariño-Ramírez, I King Jordan, David Landsman
Journal: Genome biology (2006)

Core histone genes are periodically expressed along the cell cycle and peak during S phase. Core histone gene expression is deeply evolutionarily conserved from the yeast Saccharomyces cerevisiae to human. We evaluated the evolutionary dynamics of the specific regulatory mechanisms that give rise to the conserved histone regulatory phenotype. In contrast to the conservation of core histone gene expression patterns, the core histone regulatory machinery is highly divergent between species. There has been substantial evolutionary turnover of cis-regulatory sequence motifs along with the transcription factors that bind them. The regulatory mechanisms employed by members of the four core histone families are more similar within species than within gene families. The presence of species-specific histone regulatory mechanisms is opposite to what is seen at the protein sequence level. Core histone proteins are more similar within families, irrespective of their species of origin, than between families, which is consistent with the shared common ancestry of the members of individual histone families. Structure and sequence comparisons between histone families reveal that H2A and H2B form one related group whereas H3 and H4 form a distinct group, which is consistent with the nucleosome assembly dynamics. The dissonance between the evolutionary conservation of the core histone gene regulatory phenotypes and the divergence of their regulatory mechanisms indicates a highly dynamic mode of regulatory evolution. This distinct mode of regulatory evolution is probably facilitated by a solution space for promoter sequences, in terms of functionally viable cis-regulatory sites, that is substantially greater than that of protein sequences.
Sodium Channel Defects in Myotonia and Periodic Paralysis
Authors: Stephen C. Cannon
Journal: Annual Review of Neuroscience (1996)

Myotonias and periodic paralyses constitute a diverse group of inherited disorders of muscle in which the primary defect is an alteration in the electrical excitability of the muscle fiber. The ion channel defects underlying these excitability derangements have recently been elucidated at the molecular and functional levels. This review focuses on sodium channel mutations that disrupt inactivation and thereby cause both the enhanced excitability of myotonia (muscle stiffness due to repetitive discharges) and the inexcitability resulting from depolarization during attacks of paralysis.
Quality of Care in U.S. Hospitals as Reflected by Standardized Measures, 2002–2004
Authors: Scott C. Williams, Stephen P. Schmaltz, David J. Morton, Richard G. Koss, Jerod M. Loeb
Journal: New England Journal of Medicine (2005)

In July 2002, the Joint Commission on Accreditation of Healthcare Organizations implemented standardized performance measures that were designed to track the performance of accredited hospitals and encourage improvement in the quality of health care.We examined hospitals' performance on 18 standardized indicators of the quality of care for acute myocardial infarction, heart failure, and pneumonia. One measure assessed a clinical outcome (death in the hospital after acute myocardial infarction), and the other 17 measures assessed processes of care. Data were collected over a two-year period in more than 3000 accredited hospitals. All participating hospitals received quarterly feedback in the form of comparative reports throughout the study.Descriptive analysis revealed a significant improvement (P<0.01) in the performance of U.S. hospitals on 15 of 18 measures, and no measure showed a significant deterioration. The magnitude of improvement ranged from 3 percent to 33 percent during the eight quarters studied. For 16 of the 17 process-of-care measures, hospitals with a low level of performance at baseline had greater improvements over the subsequent two years than hospitals with a high level of performance at baseline.Over a two-year period, we observed consistent improvement in measures reflecting the process of care for acute myocardial infarction, heart failure, and pneumonia. Both quantitative and qualitative research are needed to explore the reasons for these improvements.
Effect of ciclesonide 40 μg and 80 μg on early and late asthmatic reaction, and sputum eosinophils after allergen challenge in patients with mild asthma
Authors: G.M. Gauvreau, R.M. Watson, D.S. Postma, J.G.R. de Monchy, F. Deschesnes, L. Boulet
Journal: Journal of Allergy and Clinical Immunology (2005)
Carboxyhaemoglobin levels and inhaling habits in cigarette smokers.
Authors: N Wald, M Idle, A Bailey
Journal: Thorax (1978)

In 520 men who currently smoked only cigarettes, carboxyhaemoglobin (COHb) levels were measured as a method of estimating the extent to which cigarette smoke was inhaled and the results were compared with the smokers9 own assessment of their inhaling habits. The mean COHb level after standardising for the number of cigarettes smoked before the blood test on the day of the test was 4.0% in self-described non-inhalers. This was much higher than the mean level of 0.7% in 1891 similar non-smokers, but not very different from the standardised mean levels of 5.2%, 5.3%, and 5.6% in men who said they inhaled slightly, moderately, or deeply, respectively. The increasing trend in the COHb levels of men in the four self-described inhaling categories (nil to deep) was small but statistically highly significant. The data from this study may help to explain some of the anomalous epidemiological results regarding the relationship between self-described inhaling habits and the development of diseases associated with smoking, such as coronary heart disease and lung cancer.
Association of IL-10 polymorphism with severity of illness in community acquired pneumonia
Authors: P M Gallagher
Journal: Thorax (2003)

The influence of genetic polymorphisms of interleukin (IL)-10, tumour necrosis factor (TNF)-alpha, and IL-6 gene promoters on severity of systemic inflammatory response syndrome (SIRS) associated with community acquired pneumonia (CAP) was studied.Using PCR-RFLP analysis we analysed a -1082G/A single nucleotide polymorphism (SNP) of the anti-inflammatory IL-10 gene, a -308G/A SNP of the pro-inflammatory TNF-alpha gene and a -174G/C SNP of the IL-6 gene. Illness severity was stratified according to SIRS score, calculated by presence of up to four physiological indices: temperature, white blood cell count, heart rate and respiratory rate (non-SIRS, SIRS 2, SIRS 3, and SIRS 4).A statistically significant stepwise increase in frequency of the IL-10 G allele, associated with higher expression of the gene, was observed in patients with increasing severity of illness from non-SIRS (n=19) to SIRS 2 (n=17), SIRS 3 (n=33) and SIRS 4 (n=24). This was primarily due to a higher frequency of the GG genotype with increasing severity from non-SIRS through to SIRS 4. IL-10 G allele frequency was also increased in patients who died as a result of CAP (n=11) compared with CAP survivors (n=82) (p=0.01). No association was seen between the TNF-alpha -308G/A and IL-6 -174G/C SNPs and disease. Additionally, no interaction between all three SNP genotypes and disease severity was observed.A polymorphism affecting IL-10 expression may influence the severity of illness in patients with CAP.