tbuckley/cabot-search huggingface dataset:
Risk of skin and soft tissue infections (including shingles) in patients exposed to anti-tumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register
Authors: James B Galloway, Louise K Mercer, Alison Moseley, William G Dixon, Andrew P Ustianowski, Matthew Helbert, Kath D Watson, Mark Lunt, Kimme L Hyrich, Deborah PM Symmons
Journal: Annals of the Rheumatic Diseases (2012)

Anti-tumour necrosis factor (TNF) therapy is a mainstay of treatment in rheumatoid arthritis (RA). In 2001, BSRBR was established to evaluate the safety of these agents. This paper addresses the safety of anti-TNF therapy in RA with specific reference to serious skin and soft tissue infections (SSSI) and shingles.A cohort of anti-TNF-treated patients was recruited alongside a comparator group with active RA treated with non-biological disease-modifying antirheumatic drugs (nbDMARD). 11 881 anti-TNF and 3673 nbDMARD patients were analysed. Follow-up was by 6-monthly questionnaires to patients and clinicians. Analyses considered SSSI and shingles separately. Incidence rates (IR) were calculated and then compared using survival analyses.The crude IR for SSSI were: anti-TNF 1.6/100 patient-years (95% CI 1.4 to 1.8); nbDMARD 0.7/100 patient-years (95% CI 0.5 to 1.0) and shingles: anti-TNF 1.6/100 patient-years (95% CI 1.3 to 2.0); nbDMARD 0.8/100 patient-years (95% CI 0.6 to 1.1). Adjusted HR were SSSI 1.4 (95% CI 0.9 to 2.4), shingles 1.8 (95% CI 1.2 to 2.8). For SSSI, no significant differences were seen between anti-TNF agents. For shingles, the lowest risk was observed for adalimumab (adjusted HR vs nbDMARD) 1.5 (95% CI 1.1 to 2.0) and highest for infliximab (HR 2.2; 95% CI 1.4 to 3.4)).A significantly increased risk of shingles was observed in the anti-TNF-treated cohort. The risk of SSSI tended towards being greater with anti-TNF treatment but was not statistically significant. As with any observational dataset cause and effect cannot be established with certainty as residual confounding may remain. This finding would support the evaluation of zoster vaccination in this population.
Temporally Variable Selection on Proteolysis-Related Reproductive Tract Proteins in Drosophila
Authors: A. Wong, M. C. Turchin, M. F. Wolfner, C. F. Aquadro
Journal: Molecular Biology and Evolution (2011)

In order to gain further insight into the processes underlying rapid reproductive protein evolution, we have conducted a population genetic survey of 44 reproductive tract–expressed proteases, protease inhibitors, and targets of proteolysis in Drosophila melanogaster and Drosophila simulans. Our findings suggest that positive selection on this group of genes is temporally heterogeneous, with different patterns of selection inferred using tests sensitive at different time scales. Such variation in the strength and targets of selection through time may be expected under models of sexual conflict and/or host–pathogen interaction. Moreover, available functional information concerning the genes that show evidence of selection suggests that both sexual selection and immune processes have been important in the evolutionary history of this group of molecules.
Idiopathic osteoarthritis and contracture: causal implications
Authors: P. Jones, C. J. Alexander, J. Stewart, N. V. Lynskey
Journal: Annals of the Rheumatic Diseases (2005)

To use the known association of idiopathic osteoarthritis with contracture as a means of searching for its cause. There are currently two theories concerning this association, one assuming that the contracture is a consequence of the osteoarthritis and the other that it precedes and causes the osteoarthritis. This study tested both theories.Flexion ranges in the 12 finger joints were obtained by goniometric measurement in two samples of normal female subjects, one group with a mean age of 22 years (25 subjects) and one with a mean age of 45 years (50 subjects). The results were compared with the known regional prevalence of osteoarthritis in the finger joints of women.The older group showed evidence of reduced flexion range consistent with development of contracture in the extensor mechanism of the fingers. The distribution of the contracture showed a strong negative correlation with the regional prevalence of osteoarthritis.An early dorsal contracture develops in the fingers of normal subjects, but it is neither a consequence of nor the cause of digital osteoarthritis. The most parsimonious explanation for the association is that both contracture and idiopathic osteoarthritis are independent consequences of failure to use the full movement range. If this hypothesis is correct, the disease could be preventable.
Myocardial Fibrosis in Chronic Aortic Regurgitation
Authors: Jeffrey S. Borer, Sharada Truter, Edmund M. Herrold, Domenick J. Falcone, Magda Pena, John N. Carter, Themy F. Dumlao, Jennifer A. Lee, Phyllis G. Supino
Journal: Circulation (2002)

Background — Myocardial fibrosis is common in patients with chronic aortic regurgitation (AR). Experimentally, fibrosis with disproportionate noncollagen extracellular matrix (ECM) elements precedes and contributes to heart failure in AR. Method and Results — We assessed [ 3 H]-glucosamine and [ 3 H]-proline incorporation in ECM, variations in cardiac fibroblast (CF) gene expression, and synthesis of specific ECM proteins in CF cultured from rabbits with surgically induced chronic AR versus controls. To determine whether these variations are primary responses to AR, normal CF were exposed to mechanical strain that mimicked that of AR. Compared with normal CF, AR CF incorporated more glucosamine (1.8:1, P =0.001) into ECM, showed fibronectin gene upregulation (2.0:1, P =0.02), and synthesized more fibronectin (2:1 by Western blot, P &lt;0.06; 1.5:1 by affinity chromatography, P =0.02). Proline incorporation was unchanged by AR (1.1:1, NS); collagen synthesis was unaffected (type I, 0.9:1; type III, 1.0:1, NS). Normal CF exposed to cyclical mechanical strain during culture showed parallel results: glucosamine incorporation increased with strain (2.1:1, P &lt;0.001), proline incorporation was unaffected (1.1:1, NS), fibronectin gene expression (1.6:1, P =0.07) and fibronectin synthesis (Western analysis, 1.3:1, P &lt;0.01; chromatography, 1.9:1, NS) were upregulated. Conclusions — In AR, CF produce abnormal proportions of noncollagen ECM, specifically fibronectin, with relatively little change in collagen synthesis. At least in part, this is a primary response to strain imposed on CF by AR. Further study must relate these findings to the pathogenesis of heart failure in AR.
Purification of a 24-kD protease from apoptotic tumor cells that activates DNA fragmentation.
Authors: S C Wright, Q S Wei, J Zhong, H Zheng, D H Kinder, J W Larrick
Journal: The Journal of Experimental Medicine (1994)

We report the purification of a protease from tumor cells undergoing apoptosis that is involved in activating DNA fragmentation. Initial studies revealed that two inhibitors of serine proteases, N-1-tosylamide-2-phenylethylchloromethyl ketone and carbobenzoxy-Ala-Ala-borophe (DK120), suppressed tumor necrosis factor or ultraviolet (UV) light-induced DNA fragmentation in the U937 histiocytic lymphoma as well as UV light-induced DNA fragmentation in the BT-20 breast carcinoma, HL-60 myelocytic leukemia, and 3T3 fibroblasts. The protease was purified by affinity chromatography with DK120 as ligand and showed high activity on a synthetic substrate preferred by elastase-like enzymes (Ala-Ala-Pro-Val p-nitroanilide), but was inactive on the trypsin substrate, N-alpha-benzyloxycarbonyl-L-lysine thiobenzyl ester, or the chymotrypsin substrate, Ala-Ala-Pro-Phe p-nitroanilide. The activity of the DK120-binding protease purified from U937 cells undergoing apoptosis was increased approximately 10-fold over that recovered from normal cells. Further purification to homogeneity by heparin-Sepharose affinity chromatography followed by reverse phase high-performance liquid chromatography revealed a single band of 24 kD on a silver-stained sodium dodecyl sulfate gel. In addition to protease activity, the purified enzyme induced DNA fragmentation into multiples of 180 basepairs in isolated U937 nuclei. These findings suggest the 24-kD protease is a novel enzyme that activates DNA fragmentation in U937 cells undergoing apoptosis.
Carbon tetrachloride—induced alterations of hepatic calmodulin and free calcium levels in rats pretreated with chlordecone†
Authors: Prasada Rao S. Kodavanti, Urmila P. Kodavanti, Harihara M. Mehendale
Journal: Hepatology (1991)

Calmodulin, a low molecular weight Ca2+ binding protein, regulates a large number of cell activities including cell division. Previous studies from our laboratory indicated excessive accumulation of Ca2+ in hepatocytes succeeded by rapid glycogen breakdown and suppressed cell division in rats receiving CCl4 after previous dietary exposure to 10 ppm chlordecone. Since calmodulin plays a major role in Ca2(+)-regulated events and has been reported to be localized in mitotic apparatus during cell division, we have assessed subcellular distribution of calmodulin and estimated cytosolic phosphorylase a to indicate cytosolic free Ca2+ levels in livers of rats fed 0 ppm or 10 ppm (chlordecone) in the diet for 15 days before CCl4 (100 microliters/kg) administration to understand the role of Ca2(+)-calmodulin in chlordecone + CCl4 toxicity. Hepatotoxicity was assessed by determining serum AST and ALT succeeded by histopathological observations of liver sections. Serum aminotransferases were significantly elevated 6 hr after CCl4 administration to normal rats and returned to control level by 24 hr. However, serum AST and ALT elevations were severalfold higher, and progressive increase was observed starting 4 hr after CCl4 administration to chlordecone rats. Histopathological observations of liver sections for necrotic, swollen and lipid-laden cells provided findings commensurate with the serum enzyme data. These data indicate that normal rats do recover from CCl4 hepatotoxicity. However, the CCl4 hepatotoxicity is progressive in chlordecone rats without recovery. In normal rats, CCl4 administration resulted in a slight increase in phosphorylase a starting at 6 hr.(ABSTRACT TRUNCATED AT 250 WORDS)
Voxel-based meta-analysis of grey matter changes in Alzheimer’s disease
Authors: Wen-Ying Wang, Jin-Tai Yu, Yong Liu, Rui-Hua Yin, Hui-Fu Wang, Jun Wang, Lin Tan, Joaquim Radua, Lan Tan
Journal: Translational Neurodegeneration (2015)

Voxel-based morphometry (VBM) using structural brain MRI has been widely used for the assessment of impairment in Alzheimer's disease (AD), but previous studies in VBM studies on AD remain inconsistent.We conducted meta-analyses to integrate the reported studies to determine the consistent grey matter alterations in AD based on VBM method.The PubMed, ISI Web of Science, EMBASE and Medline database were searched for articles between 1995 and June 2014. Manual searches were also conducted, and authors of studies were contacted for additional data. Coordinates were extracted from clusters with significant grey matter difference between AD patients and healthy controls (HC). Meta-analysis was performed using a new improved voxel-based meta-analytic method, Effect Size Signed Differential Mapping (ES-SDM).Thirty data-sets comprising 960 subjects with AD and 1195 HC met inclusion criteria. Grey matter volume (GMV) reduction at 334 coordinates in AD and no GMV increase were found in the current meta-analysis. Significant reductions in GMV were robustly localized in the limbic regions (left parahippocampl gyrus and left posterior cingulate gyrus). In addition, there were GM decreases in right fusiform gyrus and right superior frontal gyrus. The findings remain largely unchanged in the jackknife sensitivity analyses.Our meta-analysis clearly identified GMV atrophy in AD. These findings confirm that the most prominent and replicable structural abnormalities in AD are in the limbic regions and contributes to the understanding of pathophysiology underlying AD.
In vivo confocal laser scanning microscopy of melanocytic skin tumours: diagnostic applicability using unselected tumour images
Authors: A. Gerger, R. Hofmann-Wellenhof, U. Langsenlehner, E. Richtig, S. Koller, W. Weger, V. Ahlgrimm-Siess, M. Horn, H. Samonigg, J. Smolle
Journal: British Journal of Dermatology (2008)

Background In vivo confocal laser scanning microscopy (CLSM) represents a novel imaging tool that allows the noninvasive examination of skin cancer morphology in real time at a 'quasi‐histopathological' resolution viewing microanatomical structures and individual cells. Objectives To validate diagnostic confocal examination of melanocytic skin tumours using unselected tumour images. Methods In the present study, we used a total of 3709 unselected CLSM tumour images obtained from 20 malignant melanomas and 50 benign naevi. The entire set of images derived from each tumour was evaluated by independent observers. Classification tree analysis based on a subsample of 857 tumour images was performed to develop a diagnostic algorithm. Results Overall, sensitivity and specificity of 97·5% and 99% could be achieved by the independent observers (positive predictive value 97·5%, negative predictive value 99%). Classification tree analysis yielded a three‐step algorithm based on only three morphological CLSM features, facilitating a correct classification in 92·4% of the benign naevus images and 97·6% of melanoma images. Conclusions In vivo CLSM augurs a sea change in the way we will view skin tumour processes clinically at the bedside and merits application for use as a screening tool in skin oncology.
MPs accuse government of "dreadful" return on public money spent on new consultants' contract
Authors: A. O'Dowd
Journal: BMJ (2013)

Consultants have received significant pay rises since their contracts were renegotiated but are being far less productive, MPs have claimed.

The parliamentary public accounts committee tackled Department of Health officials over the matter during an evidence session on 18 March for an inquiry that was sparked by the report published earlier this month by the National Audit Office (NAO) on managing NHS hospital consultants.1

The health department, however, denied this view, saying services had improved and were proving to be better value for money overall.

The new contract for hospital consultants, introduced in October 2003, was designed to give a career structure and pay package to reward consultants who made the biggest contribution to the NHS.

The committee’s chair, Margaret Hodge, Labour MP for Barking, said: “The introduction of the new consultants’ contract cost the taxpayer a lot of money and benefited consultants enormously—a 24% to 28% increase in their potential rate of pay—yet …
* An interobserver agreement study of autofluorescence endoscopy in barrett's oesophagus among expert endoscopists
Authors: J. Mannath, V. Subramanian, E. Telakis, K. Lau, K. Ragunath
Journal: Gut (2011)

<h3>Introduction</h3> Autofluorescence imaging (AFI) is used as a Șred flag’ technique during Barrett9s surveillance to identify subtle abnormal lesions which are not evident in high resolution white light endoscopy (HRE). This technique was found to have significant false positive results, but the sensitivity remains high. The aim of this study was to assess the interobserver agreement in detecting dysplastic lesions and to assess the overall accuracy of AFI among expert endoscopists. <h3>Methods</h3> Anonymised AFI and HRE images were prospectively collected from patients undergoing Barrett9s surveillance and dysplasia work-up. The AFI images were presented on power point in random order, followed by corresponding HRE and AFI images in a second folder. Three expert endoscopists (&gt;150 AF endoscopies) scored the work sheet on separate occasions after an automated training presentation. The interobserver agreement was calculated using κ values (bias corrected) and the accuracy was calculated with histology as gold standard. <h3>Results</h3> 74 sets of anonymised white light and AFI images were prospectively collected from 63 patients (48 males, mean age 69). The interobserver agreement for number of AF lesions noted was fair with a κ value of 0.39 (95% CI 0.28 to 0.52) for AFI images which improved significantly (p=0.04) to moderate κ (0.57 and 95% CI 0.44 to 0.7) when corresponding AFI and HRE images are presented side by side. The interobserver agreement for the quadrant with most significant AF lesion was moderate with a κ of 0.48 (95% CI 0.37 to 0.6) which improved (p=0.08) to substantial κ 0.62 (95% CI 0.50 to 0.72) when corresponding images were presented. The sensitivity for dysplasia detection was 0.75 (95% CI −0.68 to 0.81) and 0.84 (95% CI 0.78 to 0.89) using AFI images alone and using corresponding images respectively. Similarly, the specificity was 0.76 (95% CI 0.71 to 0.81) and 0.85 (95% CI 0.8 to 0.89). The overall accuracy of detecting dysplasia was 0.76 (95% CI 0.7 to 0.81) using AFI images alone and 0.85 (95% CI 0.79 to 0.89) using corresponding HRE and AFI images. <h3>Conclusion</h3> The interobserver agreement for dysplasia detection in Barrett9s oesophagus using AFI images alone is only moderate among expert endoscopists, although it improved with addition of HRE. The overall accuracy of dysplasia using AF imaging was reasonable. Better understanding and recognition of what constitutes an AF positive signal on the endoscopic images is needed to improve this technique.
Breast Cancer Risk in Women With Abnormal Cytology in Nipple Aspirates of Breast Fluid
Authors: M. R. Wrensch, N. L. Petrakis, R. Miike, E. B. King, K. Chew, J. Neuhaus, M. M. Lee, M. Rhys
Journal: JNCI Journal of the National Cancer Institute (2001)

We previously showed that women with abnormal cytology in breast fluid obtained by nipple aspiration had an increased relative risk (RR) of breast cancer compared with women from whom fluid was not obtained and with women whose fluid had normal cytology. This study extends the follow-up in the original study group (n = 4046) and presents the first follow-up for a second group of women (n = 3627).We collected nipple aspirate fluid from women in the San Francisco Bay Area during the period from 1972 through 1991, classified the women according to the most severe epithelial cytology observed in fluid specimens, and determined breast cancer incidence through March 1999. We estimated RRs for breast cancer using Cox regressions, adjusting for age and year of study entry. All statistical tests were two-sided.For women in the first and second study groups, the median years of follow-up were 21 years and 9 years, respectively, and breast cancer incidences were 7.8% (285 cases in the 3633 women for whom breast cancer status could be determined) and 3.5% (115 of 3271), respectively. Compared with women from whom no fluid was obtained, whose incidences of breast cancer were 4.7% (39 of 825) and 3.3% (65 of 1950) for those in group 1 and group 2, respectively, incidences and adjusted RRs were 8.1% (34 of 422), with RR = 1.4 (95% confidence interval [CI] = 0.9 to 2.3), and 0% (0 of 31), respectively, for those with unsatisfactory aspirate specimens and 8.2% (148 of 1816), with RR = 1.6 (95% CI = 1.1 to 2.3), and 3.1% (25 of 811), with RR = 1.2 (95% CI = 0.8 to 2.0), respectively, for those with normal cytology in aspirates. Compared with women from whom no fluid was obtained, incidences and adjusted RRs for women in group 1 with epithelial hyperplasia and atypical hyperplasia in aspirates were 10.8% (52 of 483), with RR = 2.4 (95% CI = 1.6 to 3.7), and 13.8% (12 of 87), with RR = 2.8 (95% CI = 1.5 to 5.5), respectively, while those for women in group 2 were 5.5% (25 of 457) and 0% (0 of 22), respectively, with a combined RR = 2.0 (95% CI = 1.3 to 3.3).The results obtained with the newly followed women independently confirmed previous findings that women with abnormal cytology in nipple aspirates of breast fluid have an increased risk of breast cancer.
Morphologic and Functional Magnetic Resonance Imaging of Renal Artery Stenosis
Authors: Stefan O. Schoenberg, Michael V. Knopp, Frank Londy, Sumati Krishnan, Ivan Zuna, Nicole Lang, Marco Essig, Hans Hawighorst, Jeffrey H. Maki, David Stafford-Johnson, Friedrich Kallinowski, Thomas L. Chenevert, Martin R. Prince
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. The effect of combined morphologic and functional magnetic resonance (MR) imaging on the interobserver and intermodality variability for the grading of renal artery stenosis is assessed. In a randomized, blinded tricenter analysis, seven readers evaluated 43 renal arteries on x-ray digital subtraction angiography (DSA), 3D-Gadolinium MR angiography (3D-Gd-MRA), cine phase-contrast flow measurement (PC-flow), and a combined analysis of the last two. Interobserver variability was assessed for the grading of renal artery stenosis as well as regional vessel visibility. Intermodality variability for stenosis grading was analyzed in cases in which the readers agreed on the degree of stenosis in DSA. DSA had a substantial interobserver variability for the grading of stenosis (mean κ κ 0.64). 3D-Gd-MRA revealed a slightly improved interobserver variability but incorrectly graded 6 of 34 stenoses on a two-point scale (<50%, ≥50%). The combined approach of 3D-Gd-MRA and PC-flow revealed the best (P = 0.0003) interobserver variability (median κ = 0.75) and almost perfect intermodality agreement with DSA (97% of cases). These findings were confirmed in a prospective analysis of 97 renal arteries. The vessel visibility of the renal artery ostium was significantly better in 3D-Gd-MRA than in DSA, whereas the visibility of the hilar and intrarenal vessels was significantly worse (P = 0.0001). A combined morphologic and functional MR examination significantly reduces interobserver variability and offers reliable and reproducible grading of renal artery stenosis based on stenosis morphology and hemodynamic changes. It can be considered a safe and noninvasive alternative for diagnostic DSA in cases that do not require assessment of intrarenal vessels.
Tumor Infection by Oncolytic Reovirus Primes Adaptive Antitumor Immunity
Authors: Robin J. Prestwich, Fiona Errington, Elizabeth J. Ilett, Ruth S.M. Morgan, Karen J. Scott, Timothy Kottke, Jill Thompson, Ewan E. Morrison, Kevin J. Harrington, Hardev S. Pandha, Peter J. Selby, Richard G. Vile, Alan A. Melcher
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Early clinical trials are under way exploring the direct oncolytic potential of reovirus. This study addresses whether tumor infection by reovirus is also able to generate bystander, adaptive antitumor immunity. Experimental Design: Reovirus was delivered intravenously to C57BL/6 mice bearing lymph node metastases from the murine melanoma, B16-tk, with assessment of nodal metastatic clearance, priming of antitumor immunity against the tumor-associated antigen tyrosinase-related protein-2, and cytokine responses. In an in vitro human system, the effect of reovirus infection on the ability of Mel888 melanoma cells to activate and load dendritic cells for cytotoxic lymphocyte (CTL) priming was investigated. Results: In the murine model, a single intravenous dose of reovirus reduced metastatic lymph node burden and induced antitumor immunity (splenocyte response to tyrosinase-related protein-2 and interleukin-12 production in disaggregated lymph nodes). In vitro human assays revealed that uninfected Mel888 cells failed to induce dendritic cell maturation or support priming of an anti-Mel888 CTL response. In contrast, reovirus-infected Mel888 cells (reo-Mel) matured dendritic cells in a reovirus dose-dependent manner. When cultured with autologous peripheral blood lymphocytes, dendritic cells loaded with reo-Mel induced lymphocyte expansion, IFN-γ production, specific anti-Mel888 cell cytotoxicity, and cross-primed CD8+ T cells specific against the human tumor-associated antigen MART-1. Conclusion: Reovirus infection of tumor cells reduces metastatic disease burden and primes antitumor immunity. Future clinical trials should be designed to explore both direct cytotoxic and immunotherapeutic effects of reovirus.