tbuckley/cabot-search huggingface dataset:
Accumulation of leukotriene C4 and histamine in human allergic skin reactions.
Authors: S F Talbot, P C Atkins, E J Goetzl, B Zweiman
Journal: Journal of Clinical Investigation (1985)

To determine whether lipoxygenase products of arachidonic acid metabolism are released in vivo during human allergic cutaneous reactions, we serially assayed chamber fluid placed over denuded skin sites for the presence of both C-6 peptide leukotrienes (e.g., LTC4, LTD4, and LTE4) and leukotriene B4 (LTB4), using radioimmune assay and HPLC separation, and compared it to histamine (assayed radioenzymatically) in 13 atopic and two nonatopic volunteers. Skin chamber sites challenged with ragweed or grass pollen antigen (250-750 protein nitrogen units/ml) for the first hour and phosphate-buffered saline (PBS) for the next 3 h were assayed hourly and compared to sites challenged with PBS alone. As assessed by HPLC, LTC4 composed greater than 85% of the C-6 peptide leukotriene released at any skin site, whereas little LTD4 or LTE4 was detected. LTC4 was present in significantly greater concentrations at antigen sites as compared to PBS-challenged sites throughout the 4-h period. Minimal concentrations of LTB4 were found throughout this time period and were not different at antigen or PBS sites. Histamine was present in significantly greater concentrations at antigen rather than PBS sites, but the pattern of release was different from that of LTC4. Peak histamine release invariably occurred during the first hour and decreased progressively thereafter, whereas the greatest amounts of LTC4 were detected during the 2nd to 4th hours. The amount of LTC4 accumulating at the site was dependent upon the dosage of antigen used in the epicutaneous challenge. We have demonstrated in this study that of the leukotrienes assessed LTC4 is released in the greatest quantity in situ during in vivo allergic cutaneous reactions and that it is present at such sites for at least 4 h after antigen challenge. Since intradermal injection of LTC4 in humans induces wheal and flare responses that persist for hours, our findings support the hypothesis that LTC4 is an important mediator of human allergic skin reactions.
The current state of hepatology training in UK - results from a national trainee survey
Authors: I. Patanwala, A. Heycock, M. Hudson
Journal: Gut (2011)

Introduction Half of all gastroenterologists in DGH in a recent study had not received any ‘pure’ hepatology training and yet 20% of their workload was related to the management of liver disease.[1][1] There is, currently, no data on the quantity, quality and effectiveness of post graduate hepatology training in the UK. Methods We used an online questionnaire emailed to all gastroenterology trainees in the UK in 2010 to identify the proportion of gastroenterology trainees that wish to pursue a career in hepatology or deliver liver services as a gastroenterologist with a special interest in hepatology, estimate the amount of hepatology training received by trainees and where this is delivered, establish if trainees felt that hepatology training in the UK is adequate and identify factors that dissuade trainees from pursuing an interest in hepatology. Results 58% responded. Respondents were predominantly male (68%) with 1 in 5 trainees wishing to work part time as consultants. Female trainees were significantly more likely to prefer part time work (42% vs 8%, p = 0.000, Fisher's exact test). 54% of all trainees (CI 48% to 60%) wished to have a role in delivering specific liver services as a part of their consultant job profile ([figure 1][2]). 25% (CI 15% to 37%) of trainees in their fifth year or more of training had not spent any time training in unit that provides comprehensive specialist hepatology services. Median time spent time in a hepatology unit by those that had done so was 7.8 months. One third of trainees do not think that there are adequate training opportunities in their regional rotations to achieve specialist level of competence in advanced hepatology or academic hepatology (31%, CI 26% to 37% and 28% CI 22% to 33%). 20% of trainees (CI 15% to 26%) stated that the hepatology training they will have received during their programmed rotation will be inadequate in helping them to confidently manage hepatological problems as a consultant. One in three trainees (32%, CI 26% to 40%) is dissuaded from taking up hepatology as a career option. Inadequate training in hepatology, relocating from their region to avail of such training, a lack of prospective consultant level jobs and being excluded from colonoscopy were cited as the top reasons. 85% of all trainees (CI 79% to 89%) felt that their current training program could be improved (see [figure 1][2]). ![Figure 1][3]</img> Figure 1 OC-030 Trainee preferred consultant job profile with regards to hepatology service delivery Conclusion More than half of current gastroenterology trainees in the UK wish to manage liver disease as consultants although a significant proportion feel that current hepatology training is suboptimal. A national strategy aimed at improving and standardising such training in every region is urgently needed. [1]: #aff-1 [2]: #F1 [3]: pending:yes
Rapid reduction in tenosynovitis of the wrist and fingers evaluated by MRI in patients with rheumatoid arthritis after treatment with etanercept
Authors: M Pilar Lisbona, Joan Maymó, Javier Perich, Miriam Almirall, Jordi Carbonell
Journal: Annals of the Rheumatic Diseases (2010)

Objective To assess the efficacy of etanercept in reducing tenosynovitis evaluated by MRI of the hand (h-MRI) in patients with active rheumatoid arthritis (RA) refractory to disease-modifying antirheumatic drug (DMARD) after 6 weeks of treatment. Methods 31 patients with active RA defined by a disease activity score (DAS28) &gt;3.2 and synovitis in the hands were randomised into two groups: 19 patients received 50 mg weekly subcutaneous etanercept added to previous DMARD treatment and 12 patients continued with previous DMARD therapy. Clinical evaluation, blood tests, functional capacity evaluation and h-MRI were performed at the start of the investigation and at week 6. Tenosynovitis was evaluated on T1-weighted sequences with fat suppression after gadolinium as the presence of a peritendinous signal enhancement on axial images using a new method including wrist and finger tendons. The reliability, sensitivity to change and responsiveness of this method were also evaluated. Results Scores for tenosynovitis showed a significant reduction in the etanercept group compared with placebo (p=0.01) after 6 weeks of treatment. Adding MRI joint synovitis to tenosynovitis scores gave an even higher significant reduction in the etanercept group (p=0.007). A positive and statistically significant correlation between tenosynovitis and DAS28, erythrocyte sedimentation rate and C-reactive protein was found, but not with functional capacity. Responsiveness for tenosynovitis was small but was higher when joint synovitis scores were added. Conclusion Addition of etanercept significantly reduced MRI tenosynovitis of the wrist and fingers in patients with active RA refractory to DMARD treatment. The method of scoring tenosynovitis showed good reliability and moderate responsiveness.
Stem Cell Mobilization Induced by Subcutaneous Granulocyte-Colony Stimulating Factor to Improve Cardiac Regeneration After Acute ST-Elevation Myocardial Infarction
Authors: Rasmus Sejersten Ripa, Erik Jørgensen, Yongzhong Wang, Jens Jakob Thune, Jens Christian Nilsson, Lars Søndergaard, Hans Erik Johnsen, Lars Køber, Peer Grande, Jens Kastrup
Journal: Circulation (2006)

Phase 1 clinical trials of granulocyte-colony stimulating factor (G-CSF) treatment after myocardial infarction have indicated that G-CSF treatment is safe and may improve left ventricular function. This randomized, double-blind, placebo-controlled trial aimed to assess the efficacy of subcutaneous G-CSF injections on left ventricular function in patients with ST-elevation myocardial infarction.Seventy-eight patients (62 men; average age, 56 years) with ST-elevation myocardial infarction were included after successful primary percutaneous coronary stent intervention <12 hours after symptom onset. Patients were randomized to double-blind treatment with G-CSF (10 microg/kg of body weight) or placebo for 6 days. The primary end point was change in systolic wall thickening from baseline to 6 months determined by cardiac magnetic resonance imaging (MRI). An independent core laboratory analyzed all MRI examinations. Systolic wall thickening improved 17% in the infarct area in the G-CSF group and 17% in the placebo group (P=1.0). Comparable results were found in infarct border and noninfarcted myocardium. Left ventricular ejection fraction improved similarly in the 2 groups measured by both MRI (8.5 versus 8.0; P=0.9) and echocardiography (5.7 versus 3.7; P=0.7). The risk of severe clinical adverse events was not increased by G-CSF. In addition, in-stent late lumen loss and target vessel revascularization rate in the follow-up period were similar in the 2 groups.Bone marrow stem cell mobilization with subcutaneous G-CSF is safe but did not lead to further improvement in ventricular function after acute myocardial infarction compared with the recovery observed in the placebo group.
Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial
Authors: Benjamin M Scirica, Marc P Bonaca, Eugene Braunwald, Gaetano M De Ferrari, Daniel Isaza, Basil S Lewis, Felix Mehrhof, Piera A Merlini, Sabina A Murphy, Marc S Sabatine, Michal Tendera, Frans Van de Werf, Robert Wilcox, David A Morrow
Journal: The Lancet (2012)
Is the distribution of training practices appropriate for the needs of general practice?
Authors: T S Murray
Journal: BMJ (1985)

The distribution of practices that train general practitioners in the west of Scotland was examined. The concentration of training practices is lowest in conurbations that are grossly deprived. Several topics require debate: should trainees be given experience in such areas as an elective? Should the criteria for selecting training practices be similar in all areas? Should practices in deprived areas be encouraged to apply to become training practices?
The feasibility of wireless capsule endoscopy in detecting small intestinal pathology in children under the age of 8 years: a multicentre European study
Authors: A Fritscher-Ravens, P Scherbakov, P Bufler, F Torroni, T Ruuska, H Nuutinen, M Thomson, M Tabbers, P Milla
Journal: Gut (2009)

Objective: To systematically evaluate the feasibility and methodology to carry out wireless capsule endoscopy (WCE) in children <8 years to define small intestinal pathology. Design: Prospective European multicentre study with negative prior investigation. Patients and interventions: 83 children aged 1.5–7.9 years were recruited. Initially, all were offered “swallowing” (Group 1) for capsule introduction. If this failed endoscopic placement (Group 2) was used and the Roth net, Advance or custom-made introducers were compared. Outcome measures: Primary endpoint: to determine pathology; secondary endpoint: comparison of capsule introduction methods. Results: Capsule introduction: 20 (24%) children aged 4.0–7.9 years (mean, 6.9 years; 14 male) comprising Group 1 were older (p<0.025) than 63 (76%) aged 1.5–7.9 years (mean, 5.25 years; 30 male) forming Group 2. Complications: Roth net mucosal trauma in 50%; no others occurred. The available recording apparatus was inappropriate for those <3 years. Indications: gastrointestinal bleeding: n = 30 (16 positive findings: four ulcerative jejunitis, four polyps, two angiodysplasia, two blue rubber blebs, two Meckel’s diverticula, one anastomotic ulcer, one reduplication); suspected Crohn’s disease: n = 20 (11 had Crohn’s disease); abdominal pain: n = 12 (six positive findings: three Crohn’s disease, two lymphonodular hyperplasia, one blue rubber bleb); protein loss: n = 9 (four lymphangectasia); malabsorption: n = 12 (seven positive findings: six enteropathy, one ascaris). No abnormalities overall: 45%. Conclusion: WCE is feasible and safe down to the age of 1.5 years. 20 children >4 years swallowed the capsule. The Advance introducer proved superior for endoscopic placement. The pathologies encountered showed age specificity and, unlike in adolescents, obscure gastrointestinal bleeding was the commonest indication.
Soluble VEGF isoforms are essential for establishingepiphyseal vascularization and regulating chondrocyte development and survival
Authors: Christa Maes, Ingrid Stockmans, Karen Moermans, Riet Van Looveren, Nico Smets, Peter Carmeliet, Roger Bouillon, Geert Carmeliet
Journal: Journal of Clinical Investigation (2004)

VEGF is crucial for metaphyseal bone vascularization. In contrast, the angiogenic factors required for vascularization of epiphyseal cartilage are unknown, although this represents a developmentally and clinically important aspect of bone growth. The VEGF gene is alternatively transcribed into VEGF(120), VEGF(164), and VEGF(188) isoforms that differ in matrix association and receptor binding. Their role in bone development was studied in mice expressing single isoforms. Here we report that expression of only VEGF(164) or only VEGF(188) (in VEGF(188/188) mice) was sufficient for metaphyseal development. VEGF(188/188) mice, however, showed dwarfism, disrupted development of growth plates and secondary ossification centers, and knee joint dysplasia. This phenotype was at least partly due to impaired vascularization surrounding the epiphysis, resulting in ectopically increased hypoxia and massive chondrocyte apoptosis in the interior of the epiphyseal cartilage. In addition to the vascular defect, we provide in vitro evidence that the VEGF(188) isoform alone is also insufficient to regulate chondrocyte proliferation and survival responses to hypoxia. Consistent herewith, chondrocytes in or close to the hypoxic zone in VEGF(188/188) mice showed increased proliferation and decreased differentiation. These findings indicate that the insoluble VEGF(188) isoform is insufficient for establishing epiphyseal vascularization and regulating cartilage development during endochondral bone formation.
Tyrosine Kinase Inhibitor Gefitinib Enhances Topotecan Penetration of Gliomas
Authors: Angel M. Carcaboso, Mohamed A. Elmeliegy, Jun Shen, Stephen J. Juel, Ziwei M. Zhang, Christopher Calabrese, Lorraine Tracey, Christopher M. Waters, Clinton F. Stewart
Journal: Cancer Research (2010)

Gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, increases brain parenchymal extracellular fluid (ECF) accumulation of topotecan, a substrate of the ATP-binding cassette (ABC) transporters P-glycoprotein (Pgp/MDR-1) and breast cancer resistance protein (BCRP/ABCG2). The effect of modulating these transporters on topotecan penetration in gliomas has not been thoroughly studied. Thus, we performed intracerebral microdialysis on mice bearing orthotopic human gliomas (U87 and MT330) and assessed topotecan tumor ECF (tECF) penetration and the effect of gefitinib on topotecan tECF penetration and intratumor topotecan distribution. We found that topotecan penetration (P(tumor)) of U87 was 0.96 +/- 0.25 (n = 7) compared with that of contralateral brain (P(contralateral), 0.42 +/- 0.11, n = 5; P = 0.001). In MT330 tumors, P(tumor) (0.78 +/- 0.26, n = 6) and P(contralateral) (0.42 +/- 0.11, n = 5) also differed significantly (P = 0.013). Because both tumor models had disrupted blood-brain barriers and similar P(tumor) values, we used U87 and a steady-state drug administration approach to characterize the effect of gefitinib on topotecan P(tumor). At equivalent plasma topotecan exposures, we found that P(tumor) after gefitinib administration was lower. In a separate cohort of animals, we determined the volume of distribution of unbound topotecan in tumor (V(u,tumor)) and found that it was significantly higher in groups receiving gefitinib, implying that gefitinib administration leads to a greater proportion of intracellular topotecan. Our results provide crucial insights into the role that transporters play in central nervous system drug penetration and provide a better understanding of the effect of coadministration of transporter modulators on anticancer drug distribution within a tumor.
Public Attitudes Toward Participation in Cancer Clinical Trials
Authors: Robert L. Comis, Jon D. Miller, Carolyn R. Aldigé, Linda Krebs, Ellen Stoval
Journal: Journal of Clinical Oncology (2003)

Purpose: The objective of this study is to understand the attitudes of American adults toward participation in cancer clinical trials. Methods: A national probability sample of 1,000 adults aged 18 and older living in noninstitutional settings was interviewed by telephone by Harris Interactive during March and April 2000. One participant was selected from each household selected for the study. The resulting data were weighted to reflect the full adult population of the United States as reported in Current Population Reports. An Index of Participation in a Cancer Clinical Trial was computed, using a confirmatory factor analysis and converting the factor scores into a 0-to-100 scale. Results: Approximately 32% of American adults (64 million individuals) indicate that they would be very willing to participate in a cancer clinical trial if asked to do so. An additional 38% of adults (76 million individuals) scored in a range that indicates that they are inclined to participate in a cancer clinical trial if asked, but hold some questions or reservations about participation. Projected rates of diagnosis, eligibility, and recruitment indicate that substantially more patients are willing to participate than are actually accrued. Conclusion: These results indicate that the primary problem with accrual is not the attitudes of patients, but rather that the loss of potential participants is the result of the unavailability of an appropriate clinical trial and the disqualification of large numbers of patients. The pool of willing patients is further reduced by the reluctance of some physicians to engage in accrual.
Elevated levels of CD5+ B cells in spondyloarthritis patients
Authors: T Cantaert, Y Tiersma, C A Ambarus, J E Paramarta, P P Tak, L E De Rycke, D L Baeten
Journal: Annals of the Rheumatic Diseases (2010)

BackgroundWe recently proposed that spondyloarthritis (SpA) is characterised by primary alterations in the innate rather than the acquired immune system.However, SpA patients develop a strong IgM antinuclear antibody profi le upon tumour necrosis factor blockade.The characteristics of these autoantibodies are compatible with natural antibodies originating from 'innate' B cells rather than with genuine, pathogenic autoantibodies.As in mice natural autoantibodies are produced by CD5 expressing peritoneal B cells responding to innate immune signals, we aimed to quantify and characterise the CD5 B cell subset in SpA.Methods We collected peripheral blood mononuclear cells of 17 SpA patients, 11 rheumatoid arthritis (RA) patients and 20 healthy controls.Subsets and activation markers were analysed using fl ow cytometry (FacsCanto, BD) and FlowJo software.CD5 and CD5 IgD+/CD27 B cells were sorted (FACSARIA, BD) (n=HC and n=SpA).Cells were cultured for 40 h with T cell dependent (interleukin 2 (IL-2)/CD40L/anti-IgM) or T cell independent (IL-2/CpG) stimuli and analysed for the expression of the activation marker CD80.Results Total B cell numbers were similar between the three groups.Naïve (IgD+/CD27), memory (IgD-/CD27) and marginal zone-like (IgD+/CD27) B cell populations were not different between the groups.Also subclassification of the B cells according to CD38/IgD expression yielded no differences.In contrast, analysis of CD5 expression indicated an increased CD5 B cell population in SpA (22.6%) versus HC (13.6%) (p=0.048).No difference was observed between HC and R A patients.The difference in CD5 B cells between SpA and HC was most pronounced in the naïve subset (28.0%vs 12.8%, p=0.009) and the IgD+/ CD27 subset (18.4% vs 10.5%, p=0.006).Expression of the costimulatory molecules CD80 and CD86 was lowered in CD5 versus CD5 B cells both in SpA and HC (p<0.05).In contrast, expression of the early activation marker CD69 was elevated in CD5 versus CD5 B cells both in SpA and HC (p<0.05).After both T cell dependent and T cell independent stimulation, sorted CD5 naïve B cells downregulated CD80 expression (p<0.05)whereas CD5 B cells upregulated CD80 expression (p<0.05).
Developmental expression of mucin genes in the human gastrointestinal system
Authors: C J Reid, A Harris
Journal: Gut (1998)

Background and aims —Mucin glycoproteins play a key role in the normal function of the epithelium lining the gastrointestinal tract. The expression of mucin genes, MUC 3, 4, 5AC, 5B, 6, 7 , and 8 in human fetal tissues was examined to establish the localisation and age of onset of expression of each mucin gene during human development. Methods —Mucin gene expression was assayed by mRNA in situ hybridisation. Results —Expression of MUC3 was detected in the small intestine and colon from 13 weeks gestation onwards and at low levels in the main pancreatic duct at 13 weeks only. MUC4 expression was seen at a low level in the colonic epithelium from 13 weeks of gestation but not elsewhere in the gastrointestinal tract. MUC5AC mRNA was detected in the colon at 17 weeks and at high levels in the stomach at 23 weeks. MUC6 transcripts were evident in the pancreatic ducts from 13 weeks of gestation and at high levels in the stomach at 23 weeks. MUC5B , MUC7 , and MUC8 transcripts were not detected. Conclusions —Mucin genes are expressed from the early mid-trimester of gestation in the developing human fetal gastrointestinal tract.
Nutritional Epidemiology and Thyroid Hormone Metabolism
Authors: Jean Vanderpas
Journal: Annual Review of Nutrition (2006)

Severe iodine deficiency was the main cause of endemic goiter and cretinism. Most of the previously iodine-deficient areas are now supplemented, mainly with iodized salt. The geographical distribution of severe endemic areas has been progressively reduced, and at present, approximately 200 million people living in remote places are still at risk of severe iodine deficiency. International public health programs should be focused first on reaching these populations, and second on auditing and monitoring the operational work of supplementation programs. This second point is essential to prevent iodine-induced hyperthyroidism or interruptions of iodine supplement distribution, which could be catastrophic for the fetus and the young infant. Echography brings a complementary tool to clinical assessment of goiter by palpation. Inductively coupled plasma-mass spectrometry brings at least a definitive gold standard for iodine measurement and thyroid hormone measurement. Thiocyanate overload has been clearly documented as a goitrogen in Central Africa, and when associated with selenium deficiency, it may be included as risk factor for endemic myxedematous cretinism. Variable exposure to different environmental risk factors is likely the explanation of the variable distribution of two types of endemic cretinism (neurological and myxedematous), and the clinical overlap of the pathogeny of both syndromes is more important than previously described. It is possible that Kashin-Beck osteoarthropathy is another evanescent endemic disease that will disappear with the correction of iodine deficiency.