tbuckley/cabot-search huggingface dataset:
Comprehensive assessment of rheumatoid arthritis susceptibility loci in a large psoriatic arthritis cohort
Authors: John Bowes, Pauline Ho, Edw Flynn, Faisal Ali, Helena Marzo-Ortega, Laura C Coates, Rich B Warren, Ross McManus, Anthony W Ryan, David Kane, Eleanor Korendowych, Neil McHugh, Oliver FitzGerald, Jonathon Packham, Ann W Morgan, Ian N Bruce, Anne Barton
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> A number of rheumatoid arthritis (RA) susceptibility genes have been identified in recent years. Given the overlap in phenotypic expression of synovial joint inflammation between RA and psoriatic arthritis (PsA), the authors explored whether RA susceptibility genes are also associated with PsA. <h3>Methods</h3> 56 single nucleotide polymorphisms (SNPs) mapping to 41 genes previously reported as RA susceptibility loci were selected for investigation. PsA was defined as an inflammatory arthritis associated with psoriasis and subjects were recruited from the UK and Ireland. Genotyping was performed using the Sequenom MassArray platform and frequencies compared with data derived from large UK control collections. <h3>Results</h3> Significant evidence for association with susceptibility to PsA was found toa SNP mapping to the <i>REL</i> (rs13017599, p<sub>trend</sub>=5.2×10<sup>4</sup>) gene, while nominal evidence for association (p<sub>trend</sub>&lt;0.05) was found to seven other loci including <i>PLCL2</i> (rs4535211, p=1.7×10<sup>−3</sup>); <i>STAT4</i> (rs10181656, p=3.0×10<sup>−3</sup>) and the <i>AFF3</i>, <i>CD28</i>, <i>CCL21</i>, <i>IL2</i> and <i>KIF5A</i> loci. Interestingly, three SNPs demonstrated opposite effects to those reported for RA. <h3>Conclusions</h3> The <i>REL</i> gene, a key modulator of the NFκB pathway, is associated with PsA but the allele conferring risk to RA is protective in PsA suggesting that there are fundamental differences in the aetiological mechanisms underlying these two types of inflammatory arthritis.
Phase II, Randomized Trial to Compare Anastrozole Combined with Gefitinib or Placebo in Postmenopausal Women with Hormone Receptor–Positive Metastatic Breast Cancer
Authors: Massimo Cristofanilli, Vicente Valero, Aroop Mangalik, Melanie Royce, Ian Rabinowitz, Francis P. Arena, Joan F. Kroener, Elizabeth Curcio, Claire Watkins, Sarah Bacus, Elsa M. Cora, Elizabeth Anderson, Patrick J. Magill
Journal: Clinical Cancer Research (2010)

Abstract Purpose: This phase II randomized trial evaluated the efficacy and tolerability of anastrozole combined with gefitinib or anastrozole with placebo in women with hormone receptor–positive metastatic breast cancer (MBC). Experimental Design: Postmenopausal women with hormone receptor–positive measurable or evaluable MBC who had not received prior endocrine therapy for this disease stage or who developed metastatic disease during/after adjuvant tamoxifen were eligible. The primary response variable was progression-free survival (PFS) and secondary response variables included clinical benefit rate, objective response rate, overall survival, safety and tolerability, and pharmacokinetics. Tumor biomarker evaluation was an exploratory objective. Results: Forty-three patients were randomized to anastrozole plus gefitinib and 50 patients were randomized to anastrozole plus placebo of a planned total of 174 patients (enrollment was prematurely discontinued due to slow recruitment). PFS for patients receiving the combination of anastrozole and gefitinib was longer than for patients receiving anastrozole plus placebo [hazard ratio (gefitinib/placebo), 0.55; 95% confidence interval, 0.32-0.94; median PFS, 14.7 versus 8.4 months]. The clinical benefit rate was 49% versus 34%, and the objective response rate was 2% versus 12% with anastrozole plus gefitinib and anastrozole plus placebo, respectively. No evidence of interaction between baseline biomarker levels and relative treatment effect was found. No unexpected adverse events were observed. Conclusion: This small randomized study showed that anastrozole in combination with gefitinib is associated with a marked advantage in PFS compared with anastrozole plus placebo, and that the combination was tolerated in postmenopausal women with hormone receptor–positive MBC. Further investigation of epidermal growth factor receptor inhibition in combination with endocrine therapy may be warranted. Clin Cancer Res; 16(6); 1904–14
An improved method of assessing topical corticosteroid activity
Authors: H. BARNES, P.M GAYLARDE, A.P BROCK, I. SARKANY
Journal: British Journal of Dermatology (1975)

Topical application of ointment bases causes varying degrees of epidermal thickening in guinea-pigs. This is reproducible and can be accurately measured. Suppression of these changes was produced by addition of beta-methasone 17-valerate, fluocinolone acetonide, fluocinonide and hydrocortisone acetate. The inhibitory effect of these steroids was related to the type of corticosteriod, its concentration and the ointment base. The effect was still evident at extremely high dilutions of the steroids and could be measured at concentrations as low as 5 X 10(-5) % of fluocinonide in FAPG. This technique has the merits of being reproducible, sensitive and accurate. It should find a place among existing methods in assaying the efficacy of topical corticosteroids and in aiding in the selection of bases most suitable for formulation of these preparations.
The PROactive instruments to measure physical activity in patients with chronic obstructive pulmonary disease
Authors: Elena Gimeno-Santos, Yogini Raste, Heleen Demeyer, Zafeiris Louvaris, Corina de Jong, Roberto A. Rabinovich, Nicholas S. Hopkinson, Michael I. Polkey, Ioannis Vogiatzis, Maggie Tabberer, Fabienne Dobbels, Nathalie Ivanoff, Willem I. de Boer, Thys van der Molen, Karoly Kulich, Ignasi Serra, Xavier Basagaña, Thierry Troosters, Milo A. Puhan, Niklas Karlsson, Judith Garcia-Aymerich
Journal: European Respiratory Journal (2015)

No current patient-centred instrument captures all dimensions of physical activity in chronic obstructive pulmonary disease (COPD). Our objective was item reduction and initial validation of two instruments to measure physical activity in COPD. Physical activity was assessed in a 6-week, randomised, two-way cross-over, multicentre study using PROactive draft questionnaires (daily and clinical visit versions) and two activity monitors. Item reduction followed an iterative process including classical and Rasch model analyses, and input from patients and clinical experts. 236 COPD patients from five European centres were included. Results indicated the concept of physical activity in COPD had two domains, labelled “amount” and “difficulty”. After item reduction, the daily PROactive instrument comprised nine items and the clinical visit contained 14. Both demonstrated good model fit (person separation index &gt;0.7). Confirmatory factor analysis supported the bidimensional structure. Both instruments had good internal consistency (Cronbach's α&gt;0.8), test–retest reliability (intraclass correlation coefficient ≥0.9) and exhibited moderate-to-high correlations (r&gt;0.6) with related constructs and very low correlations (r&lt;0.3) with unrelated constructs, providing evidence for construct validity. Daily and clinical visit “PROactive physical activity in COPD” instruments are hybrid tools combining a short patient-reported outcome questionnaire and two activity monitor variables which provide simple, valid and reliable measures of physical activity in COPD patients.
Identification and partial characterization of an exercise-induced neutrophil chemotactic factor in bronchial asthma.
Authors: T H Lee, L Nagy, T Nagakura, M J Walport, A B Kay
Journal: Journal of Clinical Investigation (1982)

A heat-stable neutrophil chemotactic factor (NCF) has been identified in the serum of 13 atopic asthmatic subjects after treadmill exercise. Peak activity was detected at 10 min and returned to prechallenge values by 1 h. No NCF activity was detected in the sera of three nonasthmatic atopic or four normal nonatopic individuals performing the same task. NCF produced by exercise (NCFEX) had a similar time-course of release to NCF provoked by specific antigen (NCFAG). The appearance of circulating NCFEX and NCFAG closely paralleled the fall in peak expiratory flow rate/forced expiratory volume in 1 s (PEFR/FEV1). Histamine challenge in atopic asthmatics at concentrations giving a comparable change in PEFR/FEV1 to that evoked by exercise or inhaled antigen was not associated with the appearance of circulating NCF. In seven subjects NCFEX release was inhibited by prior administration of disodium cromoglycate. NCFEX and NCFAG eluted as single peaks of activity when applied separately to columns of Sephadex G-200, and both were an estimated 750,000 daltons. NCFEX and NCFAG also eluted as single peaks of activity, at between 0.15 and 0.30 M NaCl, following anion exchange chromatography on DEAE-Sephacel (pH 7.8). The isoelectric points of NCFEX and NCFAG were virtually identical (between pH 6.0 and 6.5) as determined by chromatofocusing on Polybuffer Exchanger 94. The activities of NCFEX and NCFAG were substantially reduced, in both a time- and dose-dependent fashion, after incubation with trypsin and chymotrypsin. Partially purified NCFEX and NCFAG promoted both stimulated random migration (chemokinesis) as well as directional migration (chemotaxis). These experiments indicate that NCFEX and NCFAG might be identical substances and raise the possibility that mediators by hypersensitivity are released during exercise-induced asthma in atopic subjects.
Cluster of botulism among Dutch tourists in Turkey, June 2008
Authors: C M Swaan, I M van Ouwerkerk, H J Roest
Journal: Eurosurveillance (2010)

In June 2008, three Dutch tourists participating in a mini-cruise in Turkey needed urgent repatriation for antitoxin treatment because of symptoms of botulism. Because there was a shortage of antitoxin in the Netherlands, an emergency delivery was requested from the manufacturer in Germany. An outbreak investigation was initiated into all nine cruise members, eight of whom developed symptoms. C. botulinum type B was isolated in stool culture from four of them. No other patients were notified locally. Food histories revealed locally purchased unprocessed black olives, consumed on board of the ship, as most likely source, but no left-overs were available for investigation. C. botulinum type D was detected in locally purchased canned peas, and whilst type D is not known to be a cause of human intoxication, its presence in a canned food product indicates an inadequate preserving process. With increasing tourism to areas where food-borne botulism is reported regularly special requests for botulism antitoxin may become necessary. Preparing an inventory of available reserve stock in Europe would appear to be a necessary and valuable undertaking.
Exercise during school hours when added to patient education improves outcome for 2 years in adolescent patellofemoral pain: a cluster randomised trial
Authors: M S Rathleff, E M Roos, J L Olesen, S Rasmussen
Journal: British Journal of Sports Medicine (2014)

Patellofemoral pain (PFP) is common among adolescents and associated with long-lasting pain and disability. Patient education and exercise therapy are commonly used treatments in primary and secondary care but the effect of these treatments in adolescents is unknown. We aimed to determine the effect of exercise therapy as an add-on therapy to patient education compared with education alone.121 adolescents from 15-19 years of age were cluster randomised to patient education or patient education combined with exercise therapy. Patient education covered self-management of pain and information on PFP. Exercise therapy consisted of supervised exercises on school premises (3/week for 3 months) and instructions on home-based exercises. Adherence to exercises was assessed as attendance and weekly text messages. Primary outcome measure was self-reported recovery (seven-point Likert scale) at 12 months with additional follow-ups at 3, 6 and 24 months.Adolescents randomised to patient education and exercise therapy were more likely to have recovered at 12 months (OR, 1.73, 95% CI 1.02 to 2.93, number needed to treat (NNT) of 11). Similar results were observed at 3 and 6 months (OR 1.88 and 1.43) while the effect was further increased at 24 months (OR of 2.52, NNT of 5). A higher total number of weekly exercise sessions increased the odds of recovery.In adolescent PFP, the addition of exercise therapy for 3 months was more effective than patient education alone. The effect was apparent at 3 months and increased up to 2 years. Adherence to exercises was important and improved the odds of recovery.clinicaltrials.gov reference: NCT01438762.
Prosurvival function of the cellular apoptosis susceptibility/importin-α1 transport cycle is repressed by p53 in liver cancer
Authors: Juliane Winkler, Alessandro Ori, Kerstin Holzer, Carsten Sticht, Daniel Dauch, Eva Maria Eiteneuer, Federico Pinna, Robert Geffers, Volker Ehemann, Amparo Andres-Pons, Kai Breuhahn, Thomas Longerich, Justo Lorenzo Bermejo, Norbert Gretz, Lars Zender, Peter Schirmacher, Martin Beck, Stephan Singer
Journal: Hepatology (2014)

Proteins of the karyopherin superfamily including importins and exportins represent an essential part of the nucleocytoplasmic transport machinery. However, the functional relevance and regulation of karyopherins in hepatocellular carcinoma (HCC) is poorly understood. Here we identified cellular apoptosis susceptibility (CAS, exportin-2) and its transport substrate importin-α1 (imp-α1) among significantly up-regulated transport factor genes in HCC. Disruption of the CAS/imp-α1 transport cycle by RNA i in HCC cell lines resulted in decreased tumor cell growth and increased apoptosis. The apoptotic phenotype upon CAS depletion could be recapitulated by direct knockdown of the X-linked inhibitor of apoptosis (XIAP) and partially reverted by XIAP overexpression. In addition, XIAP and CAS mRNA expression levels were correlated in HCC patient samples ( r = 0.463; P &lt; 0.01), supporting the in vivo relevance of our findings. Furthermore, quantitative mass spectrometry analyses of murine HCC samples (p53−/− versus p53+/+) indicated higher protein expression of CAS and imp-α1 in p53−/− tumors. Consistent with a role of p53 in regulating the CAS/imp-α1 transport cycle, we observed that both transport factors were repressed upon p53 induction in a p21-dependent manner. Conclusion : The CAS/imp-α1 transport cycle is linked to XIAP and is required to maintain tumor cell survival in HCC. Moreover, CAS and imp-α1 are targets of p53-mediated repression, which represents a novel aspect of p53's ability to control tumor cell growth in hepatocarcinogenesis. (Hepatology 2014;60:884–895)
Fractionated but Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect when Combined with Anti–CTLA-4 Antibody
Authors: M. Zahidunnabi Dewan, Ashley E. Galloway, Noriko Kawashima, J. Keith Dewyngaert, James S. Babb, Silvia C. Formenti, Sandra Demaria
Journal: Clinical Cancer Research (2009)

This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti-CTLA-4 antibody.TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a "primary" site that was irradiated and a "secondary" site outside the radiotherapy field. When both tumors were palpable, mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy x 1, 8 Gy x 3, or 6 Gy x 5 fractions in consecutive days) in combination or not with 9H10 monoclonal antibody against CTLA-4. Mice were followed for tumor growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model.In either of the two models tested, treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (P < 0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field, occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (P < 0.01). The frequency of CD8+ T cells showing tumor-specific IFN-gamma production was proportional to the inhibition of the secondary tumor.Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti-CTLA-4 antibody in two preclinical carcinoma models.
Incidental Detection of Concurrent Extramedullary Plasmacytoma and Amyloidoma of the Nasopharynx on [<sup>18</sup>F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography
Authors: Akihiko Yoshida, Sunita Borkar, Bhuvanesh Singh, Ronald A. Ghossein, Heiko Schöder
Journal: Journal of Clinical Oncology (2008)
Neuromuscular blocking drugs
Authors: R. Lawrie
Journal: Journal of the Royal Society of Medicine (2002)

Further to the letter from Dr Zorab (September, 2002 JRSM1), I am fortunate in having a copy of Penans by Dennis Lau, The Vanishing Nomads of Borneo. It has about 100 beautiful photos of the Penans, including pictures of the blowpipes in use, their manufacture, etc. The Penans are the principal makers and users of the blowpipe, called a sumpit. It is made from a hardwood tree. A platform is made, with a hole through which the blowpipe passes and which holds it upright. The maker stands on the platform and uses a long narrow iron bore, first from one end, then the other. To compensate for droop, he makes an upward rise in the middle of the shaft. The skill of making a blowpipe that works and is accurate is almost incredible. The job may take months. The darts are made from bamboo and coated with a poison extracted from the sap of the tacem tree (= tree of poison) and are accurate at a range of 50 feet (some say 50 yards) at which range they will kill a man. In all their spare moments, Penans make more darts, which are hardened in fire. They are kept in a gourd tied round their waist.
Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts
Authors: None Helicobacter and Cancer Collaborative Group
Journal: Gut (2001)

The magnitude of the association between Helicobacter pylori and incidence of gastric cancer is unclear. H pylori infection and the circulating antibody response can be lost with development of cancer; thus retrospective studies are subject to bias resulting from classification of cases as H pylori negative when they were infected in the past.To combine data from all case control studies nested within prospective cohorts to assess more reliably the relative risk of gastric cancer associated with H pylori infection. To investigate variation in relative risk by age, sex, cancer type and subsite, and interval between blood sampling and cancer diagnosis.Studies were eligible if blood samples for H pylori serology were collected before diagnosis of gastric cancer in cases. Identified published studies and two unpublished studies were included. Individual subject data were obtained for each. Matched odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated for the association between H pylori and gastric cancer.Twelve studies with 1228 gastric cancer cases were considered. The association with H pylori was restricted to non-cardia cancers (OR 3.0; 95% CI 2.3-3.8) and was stronger when blood samples for H pylori serology were collected 10+ years before cancer diagnosis (5.9; 3.4-10.3). H pylori infection was not associated with an altered overall risk of cardia cancer (1.0; 0.7-1.4).These results suggest that 5.9 is the best estimate of the relative risk of non-cardia cancer associated with H pylori infection and that H pylori does not increase the risk of cardia cancer. They also support the idea that when H pylori status is assessed close to cancer diagnosis, the magnitude of the non-cardia association may be underestimated.
Pitfalls in designing trials of functional dyspepsia: the ascent and demise of itopride
Authors: S. J O Veldhuyzen Van Zanten
Journal: Gut (2008)

The publication in this issue of Gut ( see page 10.1136/gut.2007.132449 ) of the results of the clinical trial programme evaluating itopride in functional dyspepsia (FD)1 needs to be applauded on two counts:

Over the last 15 years, definite progress has been made in the design, execution and data analysis of FD treatment trials. The efficacy of a limited number of treatment options has also been established. There is evidence that proton pump inhibitors (PPIs), and to a lesser extent H2 receptor antagonists (H2RAs), are efficacious in a proportion of FD patients.2–5 Importantly, the presence of heartburn appears to be a predictor of response.2 As a result, there is debate as to whether this is due to the inclusion of patients with unrecognised gastro-oesophageal reflux disease (GORD) symptoms rather than “true” FD patients.6 Consequently, there is a school of thought that non-response to a PPI should be a diagnostic criterion for a diagnosis of FD. In a small proportion of Helicobacter pylori -positive FD patients, cure of the infection will lead to a sustained improvement in symptoms with an estimated number needed to treat to obtain one success of 14.4 5 7

There has been a longstanding interest in the use of prokinetics, especially cisapride, as a treatment for FD. Unfortunately many of the cisapride studies suffered from poor study design, and there is evidence that this tended to overestimate treatment efficacy.4 5 8

Furthermore, it is possible that part of the response seen with cisapride in FD may have been related to associated heartburn symptoms.8 A systematic review on the …
Assessing Progress in Reducing the Burden of Cancer Mortality, 1985-2005
Authors: Samir Soneji, Hiram Beltrán-Sánchez, Harold C. Sox
Journal: Journal of Clinical Oncology (2014)

Measuring the effect of cancer interventions must take into account rising cancer incidence now that people live longer because of declines in mortality from cardiovascular disease (CVD). Cancer mortality rates in the population do not accomplish this objective. We sought a measure that would reveal the effects of changing mortality rates from other diseases.We obtained annual breast, colorectal, lung, and prostate cancer mortality rates from the Surveillance, Epidemiology, and End Results registries; we obtained noncancer mortality rates from national death certificates, 1975 to 2005. We used life-table methods to calculate the burden of cancer mortality as the average person-years of life lost (PYLL) as a result of cancer (cancer-specific PYLL) and quantify individual-and perhaps offsetting-contributions of the two factors that affect cancer-specific PYLL: mortality rates as a result of cancer and other-cause mortality.Falling cancer mortality rates reduced the burden of mortality from leading cancers, but increasing cancer incidence as a result of decreasing other-cause mortality rates partially offset this progress. Between 1985 and 1989 and between 2000 and 2004, the burden of lung cancer in males declined by 0.1 year of life lost. This decline reflects the sum of two effects: decreasing lung cancer mortality rates that reduced the average burden of lung cancer mortality by 0.33 years of life lost and declining other-cause mortality rates that raised it by 0.23 years. Other common cancers showed similar patterns.By using a measure that accounts for increased cancer incidence as a result of improvements in CVD mortality, we find that prior assessments have underestimated the impact of cancer interventions.