tbuckley/cabot-search huggingface dataset:
Sensitivity of hepatitis C virus to cyclosporine A depends on nonstructural proteins NS5A and NS5B
Authors: Fiona Fernandes, Daniel S. Poole, Spencer Hoover, Rannveig Middleton, Adin-Cristian Andrei, Justin Gerstner, Rob Striker
Journal: Hepatology (2007)

Abstract HCV reoccurs after liver transplantation and increases mortality. Cyclosporine, but not tacrolimus, has potent antiviral effects against HCV replication in cell culture. To determine the conditions, if any, under which HCV is susceptible to cyclosporine in vivo , we selected for cyclosporine-resistant mutant HCV in vitro . The resulting mutations were mapped to x-ray crystallographic structures and sequence databases. Mutations selected by cyclosporine were clustered in the nonstructural (NS) proteins NS5A and NS5B. Different sets of mutations in NS5A, paired with the same 2 NS5B mutations, conferred different levels of cyclosporine resistance when engineered back into the HCV replicon. Mutations in NS5B are structurally consistent with a proposed model of regulation of RNA binding by cyclophilin B (CyPB). These mutations also highlight a natural polymorphism between different HCV genotypes that correlates with the variation in response to cyclosporine A (CsA) noted in some clinical trials. Replicons engineered to have mutations in only NS5A ( P ≤ 0.0001) or only NS5B ( P = 0.002) suggest that while both NS5A or NS5B variants alter cyclosporine susceptibility, NS5A has the largest effect. Conclusion: Preexisting sequence variation could alter the effect of cyclosporine on HCV in vivo . (HEPATOLOGY 2007.)
Canadian sheet dermatitis.
Authors: R J Rycroft, E Cronin, C D Calnan
Journal: BMJ (1976)

disease it is important to recognise new primary tumours and their possible influence upon survival.The appearance in a single patient of more than one of the malignancies associated with cigarette smoking is further evidence of the hazard of this habit.We wish to thank the Medical Research Council for their continuing support (SD, MIS, and ML) and our colleagues in surgery and pathology in district hospitals in the North-west Thames Region.
Tactile agnosia and tactile apraxia: Cross talk between the action and perception streams in the anterior intraparietal area
Authors: Ferdinand Binkofski, Kathrin Reetz, Annabelle Blangero
Journal: Behavioral and Brain Sciences (2007)

Abstract In the haptic domain, a double dissociation can be proposed on the basis of neurological deficits between tactile information for action, represented by tactile apraxia, and tactile information for perception, represented by tactile agnosia. We suggest that this dissociation comes from different networks, both involving the anterior intraparietal area of the posterior parietal cortex.
Post-ERCP Pancreatitis and Hyperamylasemia: Patient-Related and Operative Risk Factors
Authors: E. Christoforidis, I. Goulimaris, I. Kanellos, K. Tsalis, C. Demetriades, D. Betsis
Journal: Endoscopy (2002)

Background and Study Aims: Previous studies on the development of post-endoscopic retrograde cholangiopancreatography (post-ERCP) hyperamylasemia and pancreatitis have focused on different risk factors, either procedure- or patient-related, and also prognostic factors, such as amylase levels together with the occurrence of pancreatic-type pain, which might be implicated. The aim of this study is to identify possible predictive risk factors and also prognostic factors in order to better organize the treatment strategy. Patients and Methods: During a 5-year period, 556 ERCP procedures were performed by the same operator. Of these, 43 procedures were excluded from the study. Data recorded from the procedures included both patient characteristics and procedure details. Patients were evaluated for pancreatic-type pain at 4 and 24 h after the procedure, and serum amylase levels were determined at 2 and 24 h after the procedure. Pancreatitis was diagnosed on the basis of both clinical and laboratory examination, while patients with hyperamylasemia were in a normal clinical condition but had high serum amylase levels. Results: Post-ERCP pancreatitis occurred after 17 procedures (3.3 %) and hyperamylasemia after 85 procedures (16.5 %). Patients who developed pancreatitis all had pancreatic-type pain together with amylase levels higher than 4 - 5 times the upper normal limit at 24 h after ERCP. There was a significant association between serum amylase levels and post-procedure pancreatic-type pain both at 4 h and 24 h after ERCP (P = 0.006). Age less than 50 years, history of relapsing pancreatitis, pancreatic duct opacification, and difficulty in obtaining bile duct cannulation all proved to be significant predictive risk factors for the development of either hyperamylasemia or pancreatitis. In contrast, additional procedures and sphincterotomy seemed to reduce the likelihood of both complications. Conclusions: Serum amylase levels higher than 4 - 5 times the normal upper limit together with the existence of pancreatic-type pain, at 24 h after ERCP, strongly suggest the occurrence of pancreatitis. When any of the predictive risk factors coexist during a procedure it would be better either to abandon the procedure and try again later or, if the situation is urgent, to have earlier recourse to an alternative, such as precut or needle-knife papillotomy.
Abstract 2821: Anti-tumor activity of ASP3026, – A novel and selective ALK inhibitor -
Authors: Sadao Kuromitsu, Masamichi Mori, Itsuro Shimada, Yutaka Kondoh, Nobuaki Shindoh, Takatoshi Soga, Takashi Furutani, Satoshi Konagai, Hideki Sakagami, Mari Nakata, Yoko Ueno, Rika Saito, Masao Sasamata, Hiroyuki Mano, Masafumi Kudou
Journal: Cancer Research (2011)

Abstract EML4-ALK is an oncogenic fusion kinase which was first identified in non-small cell lung cancer (NSCLC), and is regarded as an attractive therapeutic target for treating a subpopulation of NSCLC patients. We synthesized and screened chemical compounds utilizing an ALK kinase inhibition assay aimed at the EML4-ALK target for drug discovery, and found ASP3026, a novel and selective inhibitor for the ALK kinase. ASP3026 inhibited ALK kinase activity at an IC50 value of 3.5 nmol/L, and showed more selective ALK inhibition in a Tyr-kinase panel than PF02341066. In an anchorage independent in vitro cell growth assay, ASP3026 inhibited the growth of NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK variant 3, with an IC50 value of 64.8 nmol/L. This growth inhibition was accompanied with the decrease in phosphorylation of EML4-ALK protein, indicating that ASP3026 exerts its anti-proliferative activity through ALK kinase inhibition. The plasma and tumor concentrations of ASP3026 in mice xenografted with NCI-H2228 tumor after a 5-day repeated oral dosing of ASP3026 (10 mg/kg once daily) were determined using high-performance liquid chromatography-tandem mass spectrometry. Tmax values were 4 h in plasma and tumors. Cmax values at the corresponding doses were, respectively, 875 nmol/mL and 15500 nmol/g. A decrease of phophorylated EML4-ALK was confirmed 4 hours after a single administration of ASP3026 at 10 mg/kg by Western-blot analysis. The antitumor activities were evaluated using mice bearing subcutaneous NCI-H2228 tumor xenografts. ASP3026, administered as twice daily oral dosing for 14 days, induced dose dependent anti-tumor effects starting at 1 mg/kg with strong regression at 10, 30 and 100 mg/kg. No influence on body weights was observed in all dose range of ASP3026 treated-mice. In contrast, PF02341066 at twice daily oral dosing resulted in growth inhibition of NCI-H2228 xenografted tumors at 10 mg/kg, and tumor regression at 30 mg/kg. In addition, 100 mg/kg of PF02341066 was intolerable in this model. These results suggest that ASP3026 is a novel and selective ALK inhibitor, which is orally active, and will possibly target NSCLC patients possessing the EML4-ALK fusion. We are starting phase I clinical trials of ASP3026 in the near future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2821. doi:10.1158/1538-7445.AM2011-2821
Gerald Charles Joseph Bennett
Authors: L. Doyal
Journal: BMJ (2003)

Gerry Bennett devoted his professional and much of his personal life to the care of older people. His earliest research was concerned with clinical standards and delays in treatment. From there, and throughout the 1980s, he began to focus on the care of elderly patients, at that time a neglected specialty.​specialty.




Figure 1




He was appointed a consultant at the London Hospital in 1984. Gerry was one of a handful of campaigning geriatricians who drew attention to the need for high level specialist care and research in that field. His research on pressure ulcers led later to the establishment of the pioneering East London Wound Healing Unit, where Gerry's commitment to an interdisciplinary approach and teamwork was apparent. The four bed unit combined the work of clinical nurse specialists, dermatologists, vascular surgeons, chiropodists, and social workers. As a member of the European advisory panel on pressure ulcers, he was able to influence clinical practice outside the United Kingdom and raise the profile of geriatric medicine internationally.

Gerry's work on wounds and injuries, together with his careful attention to patient experiences, led him, in the mid-1980s, to expose the extent of abuse suffered by elderly patients. He campaigned and researched to promote greater understanding of the cause and effects of elder abuse. Again, he took this work worldwide. He was founder chairman and later president of the charity Action on Elder Abuse, and he cofounded the International Network for the Prevention of Elder Abuse (INPEA), with links in Brazil, Canada, Australia, and Spain. Gerry was the main researcher for a World Health Organization sponsored project on elder abuse in Argentina, Austria, Brazil, Canada, India, Kenya, Lebanon, and Sweden. The ensuing report, “Missing Voices,” was published in 2002. This and other work took him, and INPEA, to the United Nations Assembly on Ageing and to contribute to UN investigations into age and gender discrimination and breaches of human rights.

In 1995 Gerry became medical director of Tower Hamlets Healthcare NHS Trust. After periods as a visiting professor at the Karolinska Institute and at Queen's University, Belfast, he became professor of health care of the elderly at Barts and the London School of Medicine and Dentistry in 2000.

He leaves his lifelong companion, Hywel, and his partner, Tom.

Gerald Charles Joseph Bennett, professor of health care of the elderly Barts and the London School of Medicine and Dentistry and former medical director Tower Hamlets Healthcare NHS Trust (b 28 July 1951; q Welsh School of Medicine 1976; FRCP), d 13 April 2003.
Pulmonary vascular remodeling in pulmonary hypertension due to chronic heart failure
Authors: Juan F. Delgado, Esther Conde, Violeta Sánchez, Fernando López‐Ríos, Miguel A. Gómez‐Sánchez, Pilar Escribano, Teresa Sotelo, Agustín Gómez de la Cámara, José Cortina, Carlos S. de la Calzada
Journal: European Journal of Heart Failure (2005)
Patient Selection and Current Practice Strategy for Off-pump Coronary Artery Bypass Surgery
Authors: Mitchell J. Magee, Laura P. Coombs, Eric D. Peterson, Michael J. Mack
Journal: Circulation (2003)

Previous studies comparing off-pump coronary artery bypass surgery (OPCABG) to conventional techniques utilizing cardiopulmonary bypass (CABG-CPB) have failed to provide patient selection guidelines. We sought to determine guidelines, attempting to rectify the limitations of previous studies.A retrospective analysis of prospectively collected data from the Society of Thoracic Surgeons National Database, from January 1999 through December 2000, identified 204 602 multivessel coronary artery bypass (CABG) patients. Unadjusted and risk-adjusted odds ratios (OR) were calculated to compare OPCABG and CABG-CPB morbidity and mortality. A propensity model was developed to identify factors associated with selection for OPCABG. All off-pump patients were pair-matched with on-pump patients based on their propensity to receive an off-pump procedure. Off-pump patients, 8.8% of the total, had significantly different patient characteristics than the on-pump group. Characteristics associated with OPCABG selection included fewer diseased vessels, absence of left main disease, fewer bypass grafts, no previous CABG, older age, chronic lung disease, and renal failure. Unadjusted and risk-adjusted odds ratios indicate a significant off-pump survival benefit and decreased morbidity including stroke and renal failure in the overall group. Propensity matching also showed a significant OPCABG survival benefit [OR (95% CI) 0.83 (0.72, 0.96)]. Subgroup analysis of propensity-matched groups identified off-pump survival benefits in patients with previous CABG (OR=0.53), diabetics (OR=0.66), LVEF between 30% to 50% (OR=0.75), females (OR=0.79), and age 66 to 75 years (OR=0.80).OPCABG imparts some survival benefit to most patient subgroups. Higher risk patients including those undergoing reoperative CABG, diabetics, and the elderly may gain the most benefit.
Hydroxychloroquine sulphate in the treatment of rheumatoid arthritis: a double blind comparison of two dose regimens.
Authors: K Pavelka, K P Sen, Z Peliskova, J Vacha, K Trnavsky
Journal: Annals of the Rheumatic Diseases (1989)

A controlled, double blind, parallel group, long term study of hydroxychloroquine sulphate in the treatment of rheumatoid arthritis, comparing daily doses of 200 mg and 400 mg, is described. The trial involved 54 patients with moderate disease activity who had not previously received antimalarial drugs. Forty three patients completed the one year treatment. The groups receiving different doses were homogeneous and did not differ in any of the 25 monitored indicators. Both dose regimens were effective, and a significant reduction of disease activity was observed after one year9s treatment. Of the nine laboratory and 11 clinical indices of efficacy monitored, no statistically significant differences were reported, but in the group of patients treated with the 400 mg daily dose the number of side effects was three times greater. As there have been no reports of retinopathy with hydroxychloroquine at daily doses of 200 mg the effectiveness of this dose is of practical importance.
Lack of somatic hypermutation of IG VH genes in lymphoid malignancies with t(2;14)(p13;q32) translocation involving the BCL11A gene
Authors: R Küppers, T Sonoki, E Satterwhite, S Gesk, L Harder, DG Oscier, PW Tucker, MJS Dyer, R Siebert
Journal: Leukemia (2002)
The three paradoxes of private medicine: Summary of responses
Authors: Birte Twisselmann
Journal: BMJ (2004)

EDITOR—The online debate of Longley's personal view starts with criticism of the author, followed by attempts to understand his rationale and psychology and a general discussion of public and private healthcare systems and their political implications, ending with examples—positive and negative—of the results of their coexistence.1

Most correspondents take issue with Longley's three paradoxes: paying for health care can be disempowering, private medicine does not seem to cost anything, and the joy of clinical resolution is tainted by shameful feeling of compromise and guilt. Many find nothing wrong with paying for private …
Prevalence, Distribution, Predictors, and Outcomes of Patients With Calcified Nodules in Native Coronary Arteries
Authors: Yingjia Xu, Gary S. Mintz, Anthony Tam, John A. McPherson, Andrés Iñiguez, Jean Fajadet, Martin Fahy, Giora Weisz, Bernard De Bruyne, Patrick W. Serruys, Gregg W. Stone, Akiko Maehara
Journal: Circulation (2012)

Pathological studies suggest that calcified coronary nodules are a rare cause of thrombotic events. The frequency, distribution, predictors, and outcomes of calcified nodules have never been described.After successful stenting in 697 patients (167 female; median age, 58.1 years) with acute coronary syndromes, 3-vessel gray-scale and virtual histology intravascular ultrasound was performed in the proximal-mid segments of all 3 coronary arteries as part of a prospective, multicenter study. On the basis of recent histological validation, an independent core laboratory identified calcified nodules as distinct calcification with an irregular, protruding, and convex luminal surface. Patients were followed up for 3 years (median). Overall, 314 calcified nodules were detected in 250 of 1573 analyzable arteries (185 of 623 patients). Thus, the prevalence of calcified nodules was 17% per artery and 30% per patient. Two or more calcified nodules were detected in 48 coronary arteries (3%) in 76 patients (12%). The calcified nodules were located <40 mm from the ostium of the coronary artery in 85% of left anterior descending arteries and 86% of left circumflex arteries, whereas calcified nodules within the right coronary arteries were evenly and more distally distributed. Patients with calcified nodules were significantly older and had more plaque volume, more thick-cap fibroatheroma, but fewer nonculprit lesion major adverse events on follow-up.Calcified nodules in untreated nonculprit coronary segments in patients with acute coronary syndromes were more prevalent than previously recognized. Although their distribution mirrored the origin of most thrombotic events, calcified nodules caused fewer major adverse events during 3 years of follow-up.
Experimental models for hepatitis C viral infection
Authors: Andre Boonstra, Luc J. W. van der Laan, Thomas Vanwolleghem, Harry L. A. Janssen
Journal: Hepatology (2009)

Abstract Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. The majority of infected individuals develop a persistent infection, which is associated with a high risk of liver cirrhosis and hepatocellular carcinoma. Since its discovery 20 years ago, progress in our understanding of this virus has been suboptimal due to the lack of good model systems. However, in the past decade this has greatly accelerated with the development of various in vitro cell culture systems and in vivo small-animal models. These systems have made a major impact on the field of HCV research, and have provided important breakthroughs in our understanding of HCV infection and replication. Importantly, the in vitro cell culture systems and the small-animal models have allowed preclinical testing of numerous novel antiviral compounds for the treatment of chronic HCV infection. In this article, we give an overview of current models, discuss their limitations, and provide future perspectives for research directed at the prevention and cure of hepatitis C. (Hepatology 2009.)
Effect of Ryanodine on Sarcoplasmic Reticulum Ca <sup>2+</sup> Accumulation in Nonfailing and Failing Human Myocardium
Authors: Lynn R. Nimer, Dolores H. Needleman, Susan L. Hamilton, Judith Krall, Matthew A. Movsesian
Journal: Circulation (1995)

Background The purpose of this study was to determine whether abnormal Ca 2+ release through ryanodine-sensitive Ca 2+ channels in the sarcoplasmic reticulum might contribute to the abnormal [Ca 2+ ] i homeostasis that has been described in failing human myocardium. Methods and Results Occupancy of low-affinity ryanodine binding sites on ryanodine-sensitive Ca 2+ channels stimulates oxalate-supported, ATP-dependent Ca 2+ accumulation in sarcoplasmic reticulum–derived microsomes by inhibiting concurrent Ca 2+ efflux through these channels. We examined the effects of 0.5 mmol/L ryanodine on 45 Ca 2+ accumulation in microsomes prepared from nonfailing (n=8) and failing (n=10) human left ventricular myocardium. In the absence of ryanodine, 45 Ca 2+ accumulation reached similar levels in microsomes from nonfailing and failing hearts. Incubation with 0.5 mmol/L ryanodine caused a 52.2±6.5% increase in peak 45 Ca 2+ accumulation in microsomes from nonfailing hearts and a 24.3±4.1% increase in microsomes from failing hearts. The density of high-affinity ryanodine binding sites and the inhibition of [ 3 H]ryanodine dissociation from these sites by 0.1 mmol/L ryanodine were similar in microsomes from nonfailing and failing hearts. Conclusions These results, which demonstrate a diminished stimulation of Ca 2+ accumulation by ryanodine in sarcoplasmic reticulum–derived microsomes from failing human myocardium that could be explained by an uncoupling of the occupancy of low-affinity ryanodine binding sites from the reduction in the open probability of these channels or by concurrent Ca 2+ efflux through a ryanodine-insensitive mechanism, are evidence that increased efflux of Ca 2+ from the sarcoplasmic reticulum may contribute to the abnormal [Ca 2+ ] i homeostasis described in failing human myocardium.
Effect of Glucagon on Net Splanchnic Cyclic AMP Production in Normal and Diabetic Men
Authors: John E. Liljenquist, James D. Bomboy, Stephen B. Lewis, Bruce C. Sinclair-Smith, Philip W. Felts, William W. Lacy, Oscar B. Crofford, Grant W. Liddle
Journal: Journal of Clinical Investigation (1974)

Glucagon activates hepatic adenylate cyclase, thereby increasing acutely the liver content of cyclic AMP (cAMP) as well as the release of cAMP into the hepatic vein. Insulin, on the other hand, antagonizes this glucagon-mediated cAMP production, thus providing a hypothetical mechanism through which insulin might correct some of the metabolic abnormalities of diabetes. To study this hormonal interaction in man, net splanchnic cAMP production (NScAMPP) was investigated in normal and insulin-dependent diabetic men under basal conditions and in response to intravenous glucagon, 50 ng/kg/min for 2 h. In normals (n=19), basal hepatic vein cAMP concentration was 23.6+/-1.1 nM and NScAMPP was 1.7+/-0.6 nmol/min. Glucagon stimulated NScAMPP in four normal subjects to a peak of 99.6+/-43 nmol/min at 25 min with a subsequent fall to 12.4+/-5.1 nmol/min by 90 min despite continuing glucagon infusion. Endogenous insulin secretion was stimulated as indicated by rising levels of immunoreactive insulin and C-peptide (connecting peptide) immunoreactivity, raising the possibility that endogenous insulin might be responsible for the fall in NScAMPP that followed the initial spike. In the diabetics (n=8), basal hepatic vein cAMP concentration was 24.7+/-1.2 nM and NScAMPP was undetectable. Glucagon stimulated NScAMPP in five diabetics to a peak of 169.9+/-42.6 with a subsequent fall to 17.4+/-3.9 nmol/min by 90 min even though endogenous insulin secretion was not stimulated (no rise in C-peptide immunoreactivity). Although the mean increase in NScAMPP was greater in the diabetics, the two groups did not differ significantly.Conclusions. In normal resting man the liver is a significant source of circulating cAMP. Diabetics do not release abnormally large amounts of hepatic cAMP under basal conditions. Glucagon markedly enhances hepatic cAMP release with a spike-decline pattern in both normal and diabetic men. The decline in hepatic cAMP release despite continuing glucagon stimulation is due to factors other than a stimulation of insulin secretion.