tbuckley/cabot-search huggingface dataset:
Calcineurin activity is required for cardiac remodelling in pregnancy
Authors: Eunhee Chung, Fan Yeung, Leslie A. Leinwand
Journal: Cardiovascular Research (2013)

Calcium fluctuations and cardiac hypertrophy occur during pregnancy, but the role of the well-studied calcium-activated phosphatase, calcineurin, has not been studied in this setting. The purpose of this study was to determine whether calcineurin signalling is required for cardiac remodelling during pregnancy in mice.We first examined calcineurin expression in the heart of mice during pregnancy. We found both calcineurin levels and activity were significantly increased in early-pregnancy and decreased in late-pregnancy. Since progesterone levels start to rise in early-pregnancy, we investigated whether progesterone alone was sufficient to modulate calcineurin levels in vivo. After implantation of progesterone pellets in non-pregnant female mice, cardiac mass increased, whereas cardiac function was maintained. In addition, calcineurin levels increased, which is also consistent with early-pregnancy. To determine whether these effects were occurring in the cardiac myocytes, we treated neonatal rat ventricular myocytes (NRVMs) with pregnancy-associated sex hormones. We found that progesterone treatment, but not oestradiol, increased calcineurin levels. To obtain a functional read-out of increased calcineurin activity, we measured the activity of the transcription factor NFAT, a downstream target of calcineurin. Progesterone treatment significantly increased NFAT activity in NRVMs, and this was blocked by the calcineurin inhibitor cyclosporine A (CsA), showing that the progesterone-mediated increase in NFAT activity requires calcineurin activity. Importantly, CsA treatment of mice completely blocked pregnancy-induced cardiac hypertrophy.Our results show that calcineurin is required for pregnancy-induced cardiac hypertrophy, and that calcineurin activity in early-pregnancy is due at least in part to increased progesterone.
Correlation of Blood Type with the Presence of IgE Antibodies to Galactose-alpha-1,3-galactose (Alpha-gal): Is there a Protective Effect of Blood Group Substance B?
Authors: J. Posthumus, H. James, X. Wang, S. Commins, T.A.E. Platts-Mills
Journal: Journal of Allergy and Clinical Immunology (2010)
Influence of a Pressure Gradient Distal to Implanted Bare-Metal Stent on In-Stent Restenosis After Percutaneous Coronary Intervention
Authors: Lisette Okkels Jensen, Per Thayssen, Leif Thuesen, Henrik Steen Hansen, Jens Flensted Lassen, Henning Kelbaek, Anders Junker, Knud Noerregaard Hansen, Hans Erik Boetker, Lars Romer Krusell, Knud Erik Pedersen
Journal: Circulation (2007)

Fractional flow reserve predicts cardiac events after coronary stent implantation. The aim of the present study was to assess the 9-month angiographic in-stent restenosis rate in the setting of optimal stenting and a persisting gradient distal to the stent as assessed by a pressure wire pullback recording in the entire length of the artery.In 98 patients with angina pectoris, 1 de novo coronary lesion was treated with a bare-metal stent. After stent implantation, pressure wire measurements (P(d)=mean hyperemic coronary pressure and P(a)=mean aortic pressure) were performed in the target vessel: (1) P(d)/P(a) as distal to the artery as possible (fractional flow reserve per definition); (2) P(d)/P(a) just distal to the stent; (3) P(d)/P(a) just proximal to the stent; and (4) P(d)/P(a) at the ostium. Residual abnormal P(d)/P(a) was defined as a pressure drop between P(d)/P(a) measured at points 1 and 2. Fractional flow reserve distal to the artery after stenting was significantly lower (0.88+/-0.21 versus 0.97+/-0.05; P<0.001), and angiographic in-stent binary restenosis rate was significantly higher (44.0% versus 8.1%; P<0.001) in vessels with a residual abnormal P(d)/P(a). Residual abnormal P(d)/P(a) (odds ratio, 4.39; 95% confidence interval, 1.10 to 18.16; P=0.034), reference vessel size (odds ratio, 0.17; 95% confidence interval, 0.04 to 0.69; P=0.013), and stent length (odds ratio, 1.11; 95% confidence interval, 1.03 to 1.21; P=0.009) were predictors of angiographic in-stent restenosis after 9 months.A residual abnormal P(d)/P(a) distal to a bare-metal stent was an independent predictor of in-stent restenosis after implantation of a coronary bare-metal stent.
Conduction velocity depression and drug-induced ventricular tachyarrhythmias. Effects of lidocaine in the intact canine heart.
Authors: K P Anderson, R Walker, R L Lux, P R Ershler, R Menlove, M R Williams, R Krall, D Moddrelle
Journal: Circulation (1990)

Depression of myocardial conduction velocity can be an important mechanism of action of antiarrhythmic drugs but it can also facilitate arrhythmogenesis. We used lidocaine in an anesthetized canine preparation to address the hypothesis that drug-induced rate-dependent conduction velocity depression causes ventricular tachyarrhythmias. A closely spaced square array of 64 electrodes was used to determine conduction velocity longitudinal and transverse to epicardial ventricular fiber direction. Lidocaine caused rate-dependent decreases in conduction velocity that were proportionately greater in the longitudinal direction at the shortest pacing cycle lengths. Conduction velocity depression developed rapidly in the presence of lidocaine with a new steady state present by the second beat of the rapid train. Recovery from rate-dependent depression of conduction velocity was exponential with a time constant of 122 +/- 20 msec (mean +/- SD) in the longitudinal direction and 114 +/- 30 msec in the transverse direction; this difference was not significant. The relation between conduction velocity depression and ventricular arrhythmias was assessed by pacing for 3 minutes at cycle lengths of 1,000, 500, 300, and 250 msec, and for 1 minute at a cycle length of 200 msec. Arrhythmias did not occur in the baseline period in the dogs that received lidocaine, nor in 12 control dogs that were subjected to the same stimulation protocol except that saline was administered in place of lidocaine. Sustained polymorphic ventricular tachycardia (VT) occurred in six of 16 dogs given lidocaine. VT occurred in the presence of relatively high plasma lidocaine concentrations (8.4 +/- 2.3 micrograms/ml) and only at pacing cycle lengths of 300 msec or shorter. The dogs that developed VT demonstrated greater rate-dependent depression of conduction velocity than the other dogs, and activation patterns obtained just before the onset of VT showed marked conduction disturbances. Furthermore, QRS prolongation, loss of one-to-one capture, and increasingly distorted activation patterns preceded the onset of VT during fixed-rate pacing, suggesting progressive sodium channel block. In summary, rate-dependent conduction velocity depression and nonuniform activation were associated with VT in this model and can be responsible for some arrhythmias induced by antiarrhythmic drugs.
Postoperative Concurrent Radiotherapy and Chemotherapy for High-Risk Squamous-Cell Carcinoma of the Head and Neck
Authors: Jay S. Cooper, Thomas F. Pajak, Arlene A. Forastiere, John Jacobs, Bruce H. Campbell, Scott B. Saxman, Julie A. Kish, Harold E. Kim, Anthony J. Cmelak, Marvin Rotman, Mitchell Machtay, John F. Ensley, K.S. Clifford Chao, Christopher J. Schultz, Nancy Lee, Karen K. Fu
Journal: New England Journal of Medicine (2004)

Despite the use of resection and postoperative radiotherapy, high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed. We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control.Between September 9, 1995, and April 28, 2000, 459 patients were enrolled. After undergoing total resection of all visible and palpable disease, 231 patients were randomly assigned to receive radiotherapy alone (60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks) and 228 patients to receive the identical treatment plus concurrent cisplatin (100 mg per square meter of body-surface area intravenously on days 1, 22, and 43).After a median follow-up of 45.9 months, the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone (hazard ratio for local or regional recurrence, 0.61; 95 percent confidence interval, 0.41 to 0.91; P=0.01). The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group, as compared with 72 percent in the radiotherapy group. Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group (hazard ratio for disease or death, 0.78; 95 percent confidence interval, 0.61 to 0.99; P=0.04), but overall survival was not (hazard ratio for death, 0.84; 95 percent confidence interval, 0.65 to 1.09; P=0.19). The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group (P<0.001). Four patients who received combined therapy died as a direct result of the treatment.Among high-risk patients with resected head and neck cancer, concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival. However, the combined treatment is associated with a substantial increase in adverse effects.
The Australia antigen and role of the late Philadelphia general hospital in reducing post-transfusion hepatitis and sequelae
Authors: John R. Senior, W. Thomas London, Alton I. Sutnick
Journal: Hepatology (2011)

Baruch Blumberg, who received the Nobel Prize for Physiology or Medicine for his discovery of the Australia antigen, died on April 5, 2011. Arguably, that discovery has been the most important advance in the field of Hepatology. It led to the virtual elimination of transfusion related hepatitis B in most parts of the world and was essential to the identification of hepatitis A, C, D and E viruses. Credit for this is due Dr. Blumberg and teams in Philadelphia and Tokyo. In lieu of an Associate Editor commentary, Drs. Senior, London, and Sutnick, who were members of that remarkable team, tell us their inspiring story. (HEPATOLOGY 2011;)
Identification of an active, well-tolerated dose of pralatrexate in patients with relapsed or refractory cutaneous T-cell lymphoma
Authors: Steven M. Horwitz, Youn H. Kim, Francine Foss, Jasmine M. Zain, Patricia L. Myskowski, Mary Jo Lechowicz, David C. Fisher, Andrei R. Shustov, Nancy L. Bartlett, Maria L. Delioukina, Tony Koutsoukos, Michael E. Saunders, Owen A. O'Connor, Madeleine Duvic
Journal: Blood (2012)
Chronic Ulcer in Myelogenous Reticulosis
Authors: C. J. Polson
Journal: BMJ (1942)

Morbid Anatomy and Histology.-Asalready mentioned, the naked-eye appearances of the tumour were those of a subserous haematoma.On opening the caecum several small worms were noted lying free in the lumen; these were afterwards identified as whip-worms (Trichocephalus disnar).Pieces of tissue were taken for microscopical examination from the centre of the tumour mass, and, after embedding and section, stained with haematoxylin and eosin.The sections of the appendix and intestine showed acute and chronic inflammation, oedema, and haemorrhage.The bleeding seemed to have infiltrated both muscular layers of the intestines and was also seen in the sub- peritoneal part of the appendix.The exact site of origin of *the haemorrhage cannot be determined, and there was no evidence of tumour formation or of any specific granuloma in the sections examined (J.T. Quinlan).U.. 'ILUM... CommentaryThe condition described appears to be unusual, as a search of the literature failed to reveal an account of any similar case.The predominant feature was the large circumscribed haemorrhage in the wall of the caecum.Except for the in- flamed appendix there were no other signs of infection, and no evidence of spread of infection along the base of the appendix to the caecum.Following upon the operation, in- vestigations were made of the blood count, the bleeding, and the clotting time, but neither these nor other clinical mani- festations gave any evidence of an underlying haemorrhagic diathesis.Moreover, the whip-worms, which were lying free in the lumen of the caecum, were clearly playing no part in the aetiology.These are common enough inhabitants of that organ.Three possibilities offer themselves as likely explanations, and these may be considered in turn.Trauma.-There was no history of a blow on the abdomen or similar, violent injury as one would have expected had the haematoma been caused by direct violence.Further, owing to the mobility of the caecum a lesser degree of injury, un- noticed by the patient, could scarcely have caused the haemorrhage.
Scintigraphic detection of tumour necrosis factor in patients with rheumatoid arthritis
Authors: P Barrera
Journal: Annals of the Rheumatic Diseases (2003)

To investigate the biodistribution and specific targeting for tumour necrosis factor (TNF) of a fully human, radiolabelled anti-TNF monoclonal antibody (anti-TNF mAb) in patients with active rheumatoid arthritis (RA). To assess whether this agent is suitable for visualisation of synovitis.Ten patients with RA underwent whole body scintigraphy after administration of a tracer-subtherapeutic dose of 100 microg (99m)Tc human anti-TNF mAb. After two weeks, the procedure was repeated to assess the specificity of the radiolabelled antibody for TNF and its sensitivity for changes in inflammation. Therefore, a competition study was performed in five patients, who received excess unlabelled anti-TNF mAb before the tracer dose of (99m)Tc-anti-TNF. Another five patients received 120 mg methylprednisolone two days before the second scintigraphy.Radiolabelled anti-TNF mAb allowed clear visualisation of inflamed joints in patients with active RA with a high specificity. Concomitant administration of excess unlabelled anti-TNF reduced the joint uptake of (99m)Tc-anti-TNF mAb by a median of 25% as a percentage of the injected dose after 24 hours, whereas uptake in liver and spleen remained unchanged. Systemic corticosteroids reduced the disease activity, which was mirrored by a decreased joint uptake of the tracer. The anti-TNF mAb retained its high affinity for TNF alpha after labelling and was cleared from the circulation with an elimination half life of 48 hours. The procedure was well tolerated.Radiolabelled human anti-TNF mAb allows visualisation of synovitis in patients with RA. Joint accumulation of this agent is partly due to specific TNF targeting and is highly predictive for inflammation.
Expression of p53 in early (T1) gastric carcinoma and precancerous adjacent mucosa.
Authors: M J Brito, G T Williams, H Thompson, M I Filipe
Journal: Gut (1994)

Abnormalities of the tumour suppressor gene p53 have been shown in approximately 60% of advanced gastric adenocarcinomas and it has been suggested that the immunohistochemical finding of increased p53 expression is a prognostic marker in gastric cancer. No studies of early (T1) tumours have been reported. Over expression of p53 protein in 95 early gastric carcinomas and in adjacent mucosa was investigated using immunohistochemistry with antibody CM1. Thirty five per cent of the tumours were positive. The frequency of p53 positivity in tumours of tubular histological type (46%) was significantly higher than that in signet ring tumours (10%) (p = 0.006), and neoplasms that invaded deeply into the submucosa were more frequently positive (45%) than others (30%). Five of eight (62%) T1 tumours with lymph node metastases showed immunoreactive p53. In signet ring tumours, immunopositivity correlated with the frequency of DNA aneuploidy. p53 Over expression was also found in 15% of 26 examples of high grade dysplasia in mucosa adjacent to invasive tumours. No positivity was found in intestinal metaplasia or in normal mucosa. The findings show that immunocytochemically demonstrable over expression of p53 correlates with other morphological markers of aggressiveness in T1 gastric adenocarcinoma. The increasing frequency of p53 immunoreactivity in the sequence of high grade dysplasia-->early gastric cancer-->advanced gastric cancer supports the view that abnormalities of p53 are related to tumour progression in gastric carcinogenesis.
Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway
Authors: Wouter J de Jonge, Esmerij P van der Zanden, Frans O The, Maarten F Bijlsma, David J van Westerloo, Roelof J Bennink, Hans-Rudolf Berthoud, Satoshi Uematsu, Shizuo Akira, Rene M van den Wijngaard, Guy E Boeckxstaens
Journal: Nature Immunology (2005)
Epidoxorubicin and docetaxel as first-line chemotherapy in patients with advanced breast cancer: A multicentric phase I–II study
Authors: O. Pagani, C. Sessa, F. Nolè, D. Crivellari, D. Lombardi, B. Thürlimann, D. Hess, M. Borner, J. Bauer, G. Martinelli, R. Graffeo, M. Zucchetti, M. D'Incalci, A. Goldhirsch
Journal: Annals of Oncology (2000)
Self-reported speed of eating and 7-year risk of type 2 diabetes mellitus in middle-aged Japanese men
Authors: Masaru Sakurai, Koshi Nakamura, Katsuyuki Miura, Toshinari Takamura, Katsushi Yoshita, Shin-ya Nagasawa, Yuko Morikawa, Masao Ishizaki, Teruhiko Kido, Yuchi Naruse, Yasushi Suwazono, Satoshi Sasaki, Hideaki Nakagawa
Journal: Metabolism (2012)
Pulmonary manifestations of tuberous sclerosis in first degree relatives.
Authors: J M Slingerland, R F Grossman, D Chamberlain, C E Tremblay
Journal: Thorax (1989)

In a family with tuberous sclerosis affecting four generations a mother and daughter had the rare pulmonary manifestations of the disease. Pathologically the pulmonary disease may be the same as pulmonary lymphangioleiomyomatosis.
Cloning and functional expression of a mouse liver organic cation transporter
Authors: Richard M. Green, Kathy Lo, Coreen Sterritt, David R. Beier
Journal: Hepatology (1999)

Hepatic uptake of organic cations is essential for the metabolism and secretion of numerous endobiotics and drugs. Several hepatic organic cation transporters have been kinetically defined, yet have not been isolated or cloned. We have isolated a complementary DNA (cDNA) from both murine liver and kidney cDNA libraries ( mOct1/Slc22a1 ), and have functionally expressed it in Xenopus laevis oocytes. Although mOct1/Slc22a1 is homologous to previously cloned rat and human organic cation transporters, organic cation transport kinetics differed markedly. mOct1/Slc22a1 –RNA injection of oocytes resulted in the saturable, time– and temperature–dependent uptake of the quaternary organic cation [ 14 C]–tetraethylammonium ([ 14 C]–TEA), with a K m of 38 μmol/L. TEA uptake was inhibited by several other organic cation drugs, but was not inhibited by the organic cation n–methyl–nicotinamide (NMN), being instead stimulated by it (fourfold). [ 14 C]–TEA uptake was also stimulated by an inside–outside proton gradient. mOct1/Slc22a1 –injected oocytes transported the organic cations [ 3 H]–1–methyl–4–phenylpyridium and [ 3 H]–choline chloride, but did not transport other classes of organic compounds. mOct1/Slc22a1 encodes for a hepatic and renal organic cation transporter which may be important for the uptake and secretion of cationic drugs and endobiotics.
Use of antibiotics. Sulphonamides, co-trimoxazole, and tetracyclines.
Authors: D S Reeves, A J Bint, D W Bullock
Journal: BMJ (1978)

SulphonamidesSulphonamides are the oldest chemotherapeutic agents whose introduction can be recalled by today's practising doctors.Although this gave them precedence of use in various treatments, they suffer from having been introduced before many of the general principles of chemotherapy had been established.They therefore sometimes acquired an unjustifiably poor reputation created by misuse, particularly in respect of dosage (see below).Furthermore, long exposure has given ample opportunity for bacterial resistance to develop.The availability of many sulphonamide derivatives with closely similar generic names has caused confusion, sometimes leading to additional therapeutic problems.Details of sulphonamides, including pharmacological properties and dosages available in Britain are given in the table; sulphonamides for topical use or specialised uses (salazo- pyrin, sulphapyridine) or non-absorbed derivatives for oral use are not included.Sulphonamides all act by inhibiting an early stage of bacterial folate synthesis.Although it is usually considered that all derivatives are more or less of equal potency, perhaps because of universal cross-resistance, there are differences in activity that might be usefully exploited in conditions when effective drug
Historical Controls for Metastatic Pancreatic Cancer: Benchmarks for Planning and Analyzing Single-Arm Phase II Trials
Authors: Philip A. Philip, Kari Chansky, Michael LeBlanc, Lawrence Rubinstein, Lesley Seymour, S. Percy Ivy, Steven R. Alberts, Paul J. Catalano, John Crowley
Journal: Clinical Cancer Research (2014)

We compiled and analyzed a database of cooperative group trials in advanced pancreatic cancer to develop historical benchmarks for overall survival (OS) and progression-free survival (PFS). Such benchmarks are essential for evaluating new therapies in a single-arm setting. The analysis included patients with untreated metastatic pancreatic cancer receiving regimens that included gemcitabine, between 1995 and 2005. Prognostic baseline factors were selected by their significance in Cox regression analysis. Outlier trial arms were identified by comparing individual 6-month OS and PFS rates against the entire group. The dataset selected for the generation of OS and PFS benchmarks was then tested for intertrial arm variability using a logistic-normal model with the selected baseline prognostic factors as fixed effects and the individual trial arm as a random effect. A total of 1,132 cases from eight trials qualified. Performance status and sex were independently significant for OS, and performance status was prognostic for PFS. Outcomes for one trial (NCCTG-034A) were significantly different from the other trial arms. When this trial was excluded, the remaining trial arms were homogeneous for OS and PFS outcomes after adjusting for performance status and sex. Benchmark values for 6-month OS and PFS are reported along with a method for using these values in future study design and analysis. The benchmark survival values were generated from a dataset that was homogeneous between trials. The benchmarks can be used to enable single-arm phase II trials using a gemcitabine platform, especially under certain circumstances. Such circumstances might be when a randomized control arm is not practically feasible, an early signal of activity of an experimental agent is being explored such as in expansion cohorts of phase I studies, and in patients who are not candidates for combination cytotoxic therapy.