tbuckley/cabot-search huggingface dataset:
An approach to the development of new drugs for African trypanosomiasis.
Authors: S R Meshnick, S H Blobstein, R W Grady, A Cerami
Journal: The Journal of Experimental Medicine (1978)

The inability of the bloodstream form of Trypanosoma brucei brucei to decompose hydrogen peroxide forms the basis of our attempt to develop new pharmacological agents to kill these organisms. Approximately 1-3% of the oxygen consumed by these parasites appears in the form of hydrogen peroxide. Our previous observation that free radical initiators such as heme and hematoporphyrin D proved to be trypanocidal in vitro and in vivo, respectively, prompted this investigation into the mechanism of action of this class of compounds to enhance their therapeutic efficacy. The locus of H2O2 production within the trypanosome was examined using cell-free homogenates. Experiments described herein suggest that H2O2 is formed by the alpha-glycerol phosphate dehydrogenase in an adventitious manner, and that no enzymatic means of disposing of this potentially toxic compound are present with the organisms. Naphthoquinones were found to substantially increase the rate of both oxygen consumption and H2O2 production by trypanosomal mitochondrial preparations. Presumably, the naphthoquinones are acting as coenzyme Q analogues. The addition of sublytic concentrations of both naphthoquinones and heme leads to a synergistic lysis of the organisms in vitro. Another approach to increasing the susceptibility of T. b. brucei to free radical damage involved reduction of the intracellular concentration of glutathione. This was accomplished through the use of trypanocidal arsenicals. Melarsenoxide and heme acted synergistically in vitro, an effect which was further enhanced via addition of a naphthoquinone. Moreover, hematoporphyrin D and tryparsamide were shown to have a synergistic effect in T. b. brucei-infected mice.
β-Cell Dysfunction, Insulin Sensitivity, and Glycosuria Precede Diabetes in Hepatocyte Nuclear Factor-1α Mutation Carriers
Authors: Amanda Stride, Sian Ellard, Penny Clark, Lynette Shakespeare, Maurice Salzmann, Maggie Shepherd, Andrew T. Hattersley
Journal: Diabetes Care (2005)

OBJECTIVE—Patients with diabetes due to hepatocyte nuclear factor (HNF)-1α mutations have β-cell deficiency, insulin sensitivity, altered proinsulin levels, and a low renal threshold for glucose. It is uncertain how many of these features precede the development of diabetes. The aim of our study was to test for these characteristics in young nondiabetic HNF-1α mutation carriers. RESEARCH DESIGN AND METHODS—A total of 47 offspring from 19 extended families underwent genetic testing, a standard oral glucose tolerance test, and urine testing. RESULTS—HNF-1α mutations were found in 20 offspring, 7 with diabetes and 13 without diabetes. The 13 nondiabetic mutation carriers were compared with 27 family control subjects, who were matched for age, sex, and BMI. There was marked β-cell deficiency with reduced insulinogenic index (53.5 [31.5–90.9] vs. 226.0 [126.0–407.1], SD [range], P &amp;lt; 0.001) and area under the curve for insulin (P &amp;lt; 0.001). Insulin sensitivity was increased in mutation carriers (homeostatic model assessment of insulin sensitivity 144.6 [82.7–252.7] vs. 100 [66.9–149.4], P = 0.025). A total of 38% of mutation carriers had glycosuria at 2 h compared with 0% of control subjects (P = 0.0034). Those with glycosuria had peak glucose values that were higher than the mutations carriers without glycosuria (range 8.1–11.8 vs. 6.2–8.4 mmol/l, P = 0.002). The seven subjects with diabetes all showed glycosuria. CONCLUSIONS—We conclude that marked β-cell deficiency, increased insulin sensitivity, and a low renal threshold are present in young nondiabetic HNF-1α mutation carriers. The presence of glycosuria post–glucose load could be used to screen children of mutation carriers as it occurs in all mutation carriers with a peak glucose in the oral glucose tolerance test &amp;gt;8.4 mmol/l.
Oncogene Mutation Profiling of Pediatric Solid Tumors Reveals Significant Subsets of Embryonal Rhabdomyosarcoma and Neuroblastoma with Mutated Genes in Growth Signaling Pathways
Authors: Neerav Shukla, Nabahet Ameur, Ismail Yilmaz, Khedoudja Nafa, Chyau-Yueh Lau, Angela Marchetti, Laetitia Borsu, Frederic G. Barr, Marc Ladanyi
Journal: Clinical Cancer Research (2011)

In contrast to the numerous broad screens for oncogene mutations in adult cancers, few such screens have been conducted in pediatric solid tumors. To identify novel mutations and potential therapeutic targets in pediatric cancers, we conducted a high-throughput Sequenom-based analysis in large sets of several major pediatric solid cancers, including neuroblastoma, Ewing sarcoma, rhabdomyosarcoma (RMS), and desmoplastic small round cell tumor (DSRCT).We designed a highly multiplexed Sequenom-based assay to interrogate 275 recurrent mutations across 29 genes. Genomic DNA was extracted from 192 neuroblastoma, 75 Ewing sarcoma, 89 RMS, and 24 DSRCT samples. All mutations were verified by Sanger sequencing.Mutations were identified in 13% of neuroblastoma samples, 4% of Ewing sarcoma samples, 21.1% of RMS samples, and no DSRCT samples. ALK mutations were present in 10.4% of neuroblastoma samples. The remainder of neuroblastoma mutations involved the BRAF, RAS, and MAP2K1 genes and were absent in samples harboring ALK mutations. Mutations were more common in embryonal RMS (ERMS) samples (28.3%) than alveolar RMS (3.5%). In addition to previously identified RAS and FGFR4 mutations, we report for the first time PIK3CA and CTNNB1 (β-catenin) mutations in 5% and 3.3% of ERMS, respectively.In ERMS, Ewing sarcoma, and neuroblastoma, we identified novel occurrences of several oncogene mutations recognized as drivers in other cancers. Overall, neuroblastoma and ERMS contain significant subsets of cases with nonoverlapping mutated genes in growth signaling pathways. Tumor profiling can identify a subset of pediatric solid tumor patients as candidates for kinase inhibitors or RAS-targeted therapies.
Use of deputising services and night visit rates in general practice.
Authors: M G Sheldon, S J Harris
Journal: BMJ (1984)

Examining all of the claim forms for night visits submitted to the Nottingham Family Practitioner Committee over a three month period allowed us to calculate the night visit rate for all 184 practices in Nottinghamshire. To take all of the practices together the mean night visit rate (covering all visits requested and made between 11 00 pm and 7 00 am) was 15.5 visits per 1000 patients a year, range 1.2 to 46.1. Whether or not a deputising service is used accounted for 12% of the total variance detected, while the other factors studied, such as area of practice, patient list size, and number of partners, accounted for approximately 1% each. The local deputising service responds to 97% of night calls with a visit to the patient, whereas the patient9s own doctor is more likely to provide advice over the telephone. The ability to provide telephone advice, however, will vary according to the breakdown of the practice by age and social class.
Relation between clinical presentation, Helicobacter pylori density, interleukin 1beta and 8 production, and cagA status
Authors: Y Yamaoka, T Kodama, M Kita, J Imanishi, K Kashima, D Y Graham
Journal: Gut (1999)

<h3>BACKGROUND</h3> It is not known whether<i>cagA</i>+ <i>Helicobacter pylori</i> in duodenal ulcer (DU) have enhanced virulence compared with non-DU <i>cagA</i>+ <i>H pylori.</i> <h3>AIMS</h3> To investigate the relation between presentation, <i>H pylori</i> density, interleukin 1β (IL-1β) and IL-8 production, and<i>cagA</i> status. <h3>METHODS</h3> Fifty DU and 50 gastritis patients with <i>cagA+ H pylori</i> and 11 with <i>cagA</i>− infections were studied. Bacterial density and cytokine production were assessed using the same biopsies. Cytokine production was also measured from supernatants of medium following coculture of <i>H pylori</i> with MKN-45 cells. <h3>RESULTS</h3> There was no relation between<i> H pylori</i> density and<i>cagA </i>status. There was a dose dependent relation between mucosal cytokine levels and density of<i>cagA</i>+ <i>H pylori</i>.<i> H pylori</i> density increased to a threshold, followed by a rapid increase in cytokines and then a plateau. IL-1β and IL-8 levels in the antrum were greater in DU than in gastritis; in the corpus the cytokine level/<i>H pylori</i> differed irrespective of similar <i>H pylori</i> densities. However, cytokine production was similar in vitro, independent of presentation or biopsy site, suggesting that host factors are critical determinants of the inflammatory response. Mucosal IL-8 and IL-1β levels were low with<i>cagA</i>− and<i>cagA</i>+, <i>cagE− H pylori</i> infections. <h3>CONCLUSIONS</h3> The increase in antral IL-1β and IL-8 production and inflammation in DU is related to increased numbers of bacteria and not to an increase in cytokine production per <i>cagA</i>+ isolate. There was no evidence of enhanced virulence of <i>H pylori</i>from DU compared with <i>cagA+ </i>non-DU<i>H pylori.</i>
Influence of Primary Pancreatic Tumor Location on Efficacy and Treatment Exposure in the Mpact Trial of Nab-Paclitaxel (Nab-P) Plus Gemcitabine (Gem) Vs Gem Alone for Patients with Metastatic Pancreatic Cancer (Mpc)
Authors: W.W. Ma, J.A. López-Martín, C.S. Karapetis, P. Balcke, H. Kennecke, M. Stahl, M. Milella, F. Nugent, D. Prager, B. Lu, S. Ferrara, D. Penenberg, D. D Von Hoff
Journal: Annals of Oncology (2014)
Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency
Authors: Antonio M Almeida, Yoshiko Murakami, D Mark Layton, Peter Hillmen, Gabrielle S Sellick, Yusuke Maeda, Stephen Richards, Scott Patterson, Ioannis Kotsianidis, Luigina Mollica, Dorothy H Crawford, Alastair Baker, Michael Ferguson, Irene Roberts, Richard Houlston, Taroh Kinoshita, Anastasios Karadimitris
Journal: Nature Medicine (2006)
Use and Application of the Cuvette Densitometer as an Oximeter
Authors: DAVID C. SABISTON, EDWARD M. KHOURI, DONALD E. GREGG
Journal: Circulation Research (1957)

A method has been developed for the continuous recording of oxygen saturation in blood by the use of a cuvette densitometer. The device consists of a light source, a cuvette through which the blood flows and a photosensitive element. It is simple to operate and has an acceptable sensitivity and stability. The instrument is applicable to a number of investigative problems.
Activation and release of proteolytic kinin-forming enzymes from rat jejunal loops perfused with hyperosmolar glucose solutions.
Authors: K J Worthington, A Cuschieri
Journal: Gut (1977)

Loops of rat jejunum were perfused in vivo for one hour with de Jalon solutions of increasing glucose concentration. The esterolytic activity of the perfusate and of the extracted loop was measured using benzoyl arginine ethyl ester (BAEe) as substrate. The enzymes lactate dehydrogenase, isocitrate dehydrogenase, and acid phosphatase were measured in the perfusate to estimate the degree of cellular damage. There was a significant depletion of kallikrein from the intestine and a raised level in the perfusate during the hyperosmolar perfusions. No significant difference in the kallikrein levels was observed between the normal jejunum and the iso-osmolar perfused jejunum. Prolonged contact with hyperosmolar solutions caused some cellular damage but this effect appeared to be distinct from the release of kallikrein, which occurred very rapidly during the first 20 minutes. These results confirm that hyperosmolar intestinal contents result in the release of kinin-forming proteolytic enzymes into the circulation and suggest that this mechanism is involved in the syndrome of vasomotor dumping after gastric surgery.
Rotavirus neutralisation by human milk.
Authors: M E Thouless, A S Bryden, T H Flewett
Journal: BMJ (1977)

Rotavirus neutralisation by human milkThere has been considerable publicity recently about the benefits of breast-feeding in giving protection from infection.We have investigated the effect of mother's serum and breast milk, taken daily for five days after birth, on rotavirus infection of cells in vitro.
Improvements in anemia management with epoetin alfa: A Dutch Survey
Authors: J. van den Bosch, P. R. van de Werf, H. P. Sleeboom, B. Biesma, L. Kerkhofs, J. J. Mol, G. Ten Velde, C. F. Melissant
Journal: Journal of Clinical Oncology (2005)

8126 Background: In patients (pts) who undergo chemotherapy (CT), anemia seriously threatens the quality of life (QoL). This survey was set up to gain insight into the Dutch daily clinical practice concerning anemia management with epoetin alfa (EA; Eprex) in cancer pts treated with CT and to assess hemoglobin (Hb) development and blood transfusion (BTx) outcomes. Methods: Pts were eligible if they received CT and either received EA or had an Hb ≤ 11.3 g/dL. We collected data on Hb, BTx and EA treatment from 2 weeks before start of CT until end of CT for all pts. Data were analyzed for all pts that received EA for a minimum of 4 weeks, since that is seen as a lower limit for intent-to-treat. In some analyses pts were stratified on Hb at start of EA and number of weeks after CT start. Results: Data of 781 pts were collected. 473 Pts had EA treatment for a minimum of 4 weeks. During 8 weeks before the start of EA treatment, Hb decreased by 1.00 ± 0.13 g/dL per 4 weeks (p<0.0001*), ending up at 10.1 ± 0.13 g/dL at EA start. EA treatment corrected this Hb by 0.68 ± 0.13 g/dL per 4 weeks (p<0.0001*). Pts starting EA at an Hb >11.3 g/dL during the first week of CT (n=29), remained stable in their Hb, in contrast to pts not starting EA within the first 8 weeks of CT (n=161). The latter pts had an Hb decrease of 1.02 ± 0.10 g/dL per 4 weeks (p<0.0001*). Difference in rate between groups was significant (p<0.0001*). Starting EA during the first week of CT reduced the risk of needing a BTx by a factor of 2.3 in comparison with pts starting EA after more than 4 weeks of CT (p<0.0001; relative risk and Cochran-Mantel-Haenszel test of no difference between groups are calculated controlling for Hb at start of first cycle of CT). Conclusion: Early intervention with EA appears important for anemia prevention. Starting EA in the first week of CT when Hb <12 g/dL, will prevent a decrease in Hb and appears to reduce BTx risk. In literature relationships between Hb and QoL are described. In line with this, such a strategy would contribute to a better QoL for cancer pts who undergo CT. * Hb development was analyzed using mixed model growth curve analysis. Parameter estimates and p-values are based on restricted maximum likelihood estimation. Parameter estimates are presented with 95% confidence interval. No significant financial relationships to disclose.
A diagnostic algorithm for persistence of very early inflammatory arthritis: the utility of power Doppler ultrasound when added to conventional assessment tools
Authors: J E Freeston, R J Wakefield, P G Conaghan, E M A Hensor, S P Stewart, P Emery
Journal: Annals of the Rheumatic Diseases (2009)

Objectives: The aim of this study was to assess the value of power Doppler ultrasound (PDUS) in combination with routine management in a cohort of patients with very early inflammatory arthritis (IA). Methods: 50 patients with ⩽12 weeks of inflammatory symptoms with or without signs had clinical, laboratory and imaging assessments. Diagnosis was recorded at 12 months. Assuming a 15% pre-test probability of IA, post-test probabilities for various assessments were calculated and used to develop a diagnostic algorithm. Results: All patients positive for rheumatoid factor (RF) and/or cyclic citrullinated peptide (CCP) developed persistent IA, so the added value of PDUS was assessed in the seronegative (RF and CCP negative) group. The probability of IA in a seronegative patient was 6%. The addition of clinical and radiographic features raised the probability of IA to 30% and, with certain ultrasound features, this rose to 94%. Conclusions: In seronegative patients with early IA, combining PDUS with routine assessment can have a major impact on the certainty of diagnosis.
Familial cylindromatosis (turban tumour syndrome) gene localised to chromosome 16q12–q13: evidence for its role as a tumour suppressor gene
Authors: Patrick J. Biggs, Richard Wooster, Deborah Ford, Pam Chapman, Jonathon Mangion, Yvette Quirk, Douglas F. Easton, John Burn, Michael R. Stratton
Journal: Nature Genetics (1995)
Masitinib in advanced gastrointestinal stromal tumor (GIST) after failure of imatinib: A randomized controlled open-label trial
Authors: A. Adenis, J.-Y. Blay, B. Bui-Nguyen, O. Bouché, F. Bertucci, N. Isambert, E. Bompas, L. Chaigneau, J. Domont, I. Ray-Coquard, A. Blésius, B.A. Van Tine, V.R. Bulusu, P. Dubreuil, C.D. Mansfield, Y. Acin, A. Moussy, O. Hermine, A. Le Cesne
Journal: Annals of Oncology (2014)

Masitinib is a highly selective tyrosine kinase inhibitor with activity against the main oncogenic drivers of gastrointestinal stromal tumor (GIST). Masitinib was evaluated in patients with advanced GIST after imatinib failure or intolerance.
Pulmonary function in tropical eosinophilia
Authors: M. S. Nesarajah
Journal: Thorax (1972)

Pulmonary function studies were carried out on 23 patients with tropical eosinophilia. These showed an obstructive ventilatory defect in patients with symptoms for less than one month, and a restrictive ventilatory defect in addition to obstruction in those with symptoms for one to four months. These findings are correlated with the pathological changes observed by other workers in patients suffering from tropical eosinophilia.
Revised nomenclature and classification of inherited ichthyoses: Results of the First Ichthyosis Consensus Conference in Sorèze 2009
Authors: Vinzenz Oji, Gianluca Tadini, Masashi Akiyama, Claudine Blanchet Bardon, Christine Bodemer, Emmanuelle Bourrat, Philippe Coudiere, John J. DiGiovanna, Peter Elias, Judith Fischer, Philip Fleckman, Michal Gina, John Harper, Takashi Hashimoto, Ingrid Hausser, Hans Christian Hennies, Daniel Hohl, Alain Hovnanian, Akemi Ishida-Yamamoto, Witold K. Jacyk, Sancy Leachman, Irene Leigh, Juliette Mazereeuw-Hautier, Leonard Milstone, Fanny Morice-Picard, Amy S. Paller, Gabriele Richard, Matthias Schmuth, Hiroshi Shimizu, Eli Sprecher, Maurice Van Steensel, Alain Taïeb, Jorge R. Toro, Pierre Vabres, Anders Vahlquist, Mary Williams, Heiko Traupe
Journal: Journal of the American Academy of Dermatology (2010)
Evidence for Anti-Inflammatory Effects of Exercise in CKD
Authors: João L. Viana, George C. Kosmadakis, Emma L. Watson, Alan Bevington, John Feehally, Nicolette C. Bishop, Alice C. Smith
Journal: Journal of the American Society of Nephrology (2014)

CKD is associated with a complex state of immune dysfunction characterized by immune depression, predisposing patients to infections, and immune activation, resulting in inflammation that associates with higher risk of cardiovascular disease. Physical exercise may enhance immune function and exert anti-inflammatory effects, but such effects are unclear in CKD. We investigated the separate effects of acute and regular moderate-intensity aerobic exercise on neutrophil degranulation (elastase release), activation of T lymphocytes (CD69 expression) and monocytes (CD86 and HLA-DR expression), and plasma inflammatory markers (IL-6, IL-10, soluble TNF-receptors, and C-reactive protein) in patients with predialysis CKD. A single 30-minute (acute) bout of walking induced a normal pattern of leukocyte mobilization and had no effect on T-lymphocyte and monocyte activation but improved neutrophil responsiveness to a bacterial challenge in the postexercise period. Furthermore, acute exercise induced a systemic anti-inflammatory environment, evidenced by a marked increase in plasma IL-10 levels (peaked at 1 hour postexercise), that was most likely mediated by increased plasma IL-6 levels (peaked immediately postexercise). Six months of regular walking exercise (30 min/d for 5 times/wk) exerted anti-inflammatory effects (reduction in the ratio of plasma IL-6 to IL-10 levels) and a downregulation of T-lymphocyte and monocyte activation, but it had no effect on circulating immune cell numbers or neutrophil degranulation responses. Renal function, proteinuria, and BP were also unaffected. These findings provide compelling evidence that walking exercise is safe with regard to immune and inflammatory responses and has the potential to be an effective anti-inflammatory therapy in predialysis CKD.
The impact of peginterferon alfa-2a plus ribavirin combination therapy on health-related quality of life in chronic hepatitis C
Authors: Tarek Hassanein, Graham Cooksley, Mark Sulkowski, Coleman Smith, George Marinos, Ming-Yang Lai, Giuseppe Pastore, Rafael Trejo-Estrada, Ana Horta e Vale, Neil Wintfeld, Jesse Green
Journal: Journal of Hepatology (2004)
A role for β-melanocyte-stimulating hormone in human body-weight regulation
Authors: Heike Biebermann, Tamara R. Castañeda, Frank van Landeghem, Andreas von Deimling, Frederike Escher, Georg Brabant, Johannes Hebebrand, Anke Hinney, Matthias H. Tschöp, Annette Grüters, Heiko Krude
Journal: Cell Metabolism (2006)
Bile acids directly augment caudal related homeobox gene Cdx2 expression in oesophageal keratinocytes in Barrett's epithelium
Authors: H Kazumori
Journal: Gut (2005)

<b>Background and aims:</b> The mechanism of transformation to intestinal metaplasia in Barrett’s oesophagus has not been clarified. We investigated the effects of various bile acids on expression of the caudal related homeobox gene Cdx2 in cultured oesophageal squamous epithelial cells. In addition, morphological and histochemical changes in squamous cells to intestinal epithelial cells were studied in response to bile acid induced expression of Cdx2. <b>Methods:</b> A rat model of Barrett’s oesophagus was created by anastomosing the oesophagus and jejunum, and Cdx2 expression was investigated by immunohistochemistry. Also, the response of various bile acids on Cdx2 gene expression was studied in the human colon epithelial cell lines Caco-2 and HT-29, as well as in cultured rat oesophageal squamous epithelial cells using a Cdx2 promoter luciferase assay. In addition, primary cultured oesophageal squamous epithelial cells were transfected with Cdx2 expression vectors and their possible transformation to intestinal-type epithelial cells was investigated. <b>Results:</b> Oesophagojejunal anastomoses formed intestinal goblet cell metaplasia in rat oesophagus specimens and metaplastic epithelia strongly expressed Cdx2. When the effects of 11 types of bile acids on Cdx2 gene expression were examined, only cholic acid (CA) and dehydrocholic acid dose dependently increased Cdx2 promoter activity and Cdx2 protein production in Caco-2 and HT-29 cells, and cultured rat oesophageal keratinocytes. Results from mutation analysis of Cdx2 promoter suggested that two nuclear factor κB (NFκB) binding sites were responsible for the bile acid induced activation of the Cdx2 promoter. When bile acids were measured in oesophageal refluxate of rats with experimental Barrett’s oesophagus, the concentration of CA was found to be consistent with the experimental dose that augmented Cdx2 expression in vitro. Furthermore, transfection of the Cdx2 expression vector in cultured rat oesophageal keratinocytes induced production of intestinal-type mucin, MUC2, in cells that expressed Cdx2. <b>Conclusions:</b> We found that CA activates Cdx2 promoter via NFκB and stimulates production of Cdx2 protein in oesophageal keratinocytes with production of intestinal-type mucin. This may be one of the mechanisms of metaplasia in Barrett’s oesophagus.