tbuckley/cabot-search huggingface dataset:
A Dirichlet Process Covarion Mixture Model and Its Assessments Using Posterior Predictive Discrepancy Tests
Authors: Yan Zhou, Henner Brinkmann, Nicolas Rodrigue, Nicolas Lartillot, Hervé Philippe
Journal: Molecular Biology and Evolution (2009)

Heterotachy, the variation of substitution rate at a site across time, is a prevalent phenomenon in nucleotide and amino acid alignments, which may mislead probabilistic-based phylogenetic inferences. The covarion model is a special case of heterotachy, in which sites change between the "ON" state (allowing substitutions according to any particular model of sequence evolution) and the "OFF" state (prohibiting substitutions). In current implementations, the switch rates between ON and OFF states are homogeneous across sites, a hypothesis that has never been tested. In this study, we developed an infinite mixture model, called the covarion mixture (CM) model, which allows the covarion parameters to vary across sites, controlled by a Dirichlet process prior. Moreover, we combine the CM model with other approaches. We use a second independent Dirichlet process that models the heterogeneities of amino acid equilibrium frequencies across sites, known as the CAT model, and general rate-across-site heterogeneity is modeled by a gamma distribution. The application of the CM model to several large alignments demonstrates that the covarion parameters are significantly heterogeneous across sites. We describe posterior predictive discrepancy tests and use these to demonstrate the importance of these different elements of the models.
The contribution of ionic currents to changes in refractoriness of human atrial myocytes associated with chronic atrial fibrillation
Authors: A Workman
Journal: Cardiovascular Research (2001)

Objective: To investigate changes in human atrial single cell functional electrophysiological properties associated with chronic atrial fibrillation (AF), and the contribution to these of accompanying ion current changes. Methods: The whole cell patch clamp technique was used to record action potentials, the effective refractory period (ERP) and ion currents, in the absence and presence of drugs, in enzymatically isolated myocytes from 11 patients with chronic (<6 months) AF and 39 patients in sinus rhythm. Results: Stimulation at high rates (up to 600 beats/min) markedly shortened late repolarisation and the ERP in cells from patients in sinus rhythm, and depolarised the maximum diastolic potential (MDP). Chronic AF was associated with a reduction in the ERP at physiological rate (from 203±16 to 104±15 ms, P<0.05), and marked attenuation in rate effects on the ERP and repolarisation. The abbreviated terminal phase of repolarisation prevented fast rate-induced depolarisation of the MDP in cells from patients with AF. The density of L-type Ca2+ (ICaL) and transient outward K+ (ITO) currents was significantly reduced in cells from patients with AF (by 60–65%), whilst the inward rectifier K+ current (IK1) was increased, and the sustained outward current (IKSUS) was unaltered. Superfusion of cells from patients in sinus rhythm with nifedipine (10 micromol/l) moderately shortened repolarisation, but had no effect on the ERP (228±12 vs. 225±11 ms). 4-Aminopyridine (2 mmol/l) markedly prolonged repolarisation and the ERP (by 35%, P<0.05). However, the combination of these drugs had no effect on late repolarisation or refractoriness. Conclusion: Chronic AF in humans is associated with attenuation in adaptation of the atrial single cell ERP and MDP to fast rates, which may not be explained fully by accompanying changes in ICaL and ITO.
Paediatric gastro-oesophageal reflux: prognostic indicators from pH monitoring.
Authors: K Varty, D Evans, L Kapila
Journal: Gut (1993)

The original diagnostic 24 hour pH monitoring data in 57 children with gastro-oesophageal reflux (GOR) were retrospectively reviewed after a minimum of one year follow up. The tracings of children who responded to medical treatment were compared with those who failed to respond and required a fundoplication. Children with GOR secondary to oesophageal atresia/tracheo-oesophageal fistula and neurological conditions (n = 12) were analysed separately from those with primary GOR (n = 45). Children with primary GOR requiring a fundoplication (n = 9) had increased daytime reflux. The percentage time pH &lt; 4 was the best discriminator (21% v 7%) with a threshold of 18% giving a 92% specificity and a 70% sensitivity. For children with secondary GOR the percentage time pH &lt; 4 at night was significantly higher (29% v 3.7%) in those requiring a fundoplication (n = 5). A threshold of 18% gave an 80% specificity and an 86% sensitivity. These results show that both daytime and night time pH monitoring data can be of prognostic value in different subgroups of children with GOR. A percentage time pH &lt; 4 of greater than 18% was a useful threshold to apply when evaluating the pH monitoring data.
Design of translactam HCMV protease inhibitors as potent antivirals
Authors: Alan D. Borthwick
Journal: Medicinal Research Reviews (2005)

Human cytomegalovirus (HCMV) is an important pathogen for which there is a significant unmet medical need. New HCMV antivirals, active against novel molecular targets, are undoubtedly needed as the currently available drugs ganciclovir, cidofovir, and foscarnet, which are all viral DNA inhibitors, suffer from limited effectiveness, mainly due to the development of drug resistance, poor bioavailability, and toxicity. One of the newer molecular targets that has been exploited in the search for better drug candidates is HCMV protease. Our deltaAla HCMV protease (wild type variant with the internal cleavage site deleted) was cloned and expressed in E. coli. This viral enzyme was used to develop HCMV protease assays to evaluate potential inhibitors. The chirally pure (SRS)-alpha-methyl pyrrolidine-5,5-trans-lactam template was synthesized, which together with the natural substrate requirements of HCMV protease and detailed SAR, was used to design potent and selective mechanism based inhibitors of HCMV protease. The mechanism of action of these inhibitors of HCMV protease was investigated by ESI/MS, and the X-ray crystal structure of the HCMV protease was used to refine our selective viral enzyme inhibitors to obtain plasma stable antivirals. A novel ELISA antiviral assay was developed which, together with a cytotoxicity assay, enabled us to discover anti-HCMV drug candidates equivalent in potency to ganciclovir that had good pharmacokinetics in the dog and good brain and ocular penetration in the guinea pig.
Frequency and implications of HIV superinfection
Authors: Andrew D Redd, Thomas C Quinn, Aaron AR Tobian
Journal: The Lancet Infectious Diseases (2013)

HIV superinfection occurs when an individual with HIV is infected with a new distinct HIV viral strain. Superinfection has been reported throughout the world, and studies have recorded incidence rates of 0-7·7% per year. Use of next-generation sequencing has improved detection of superinfection, which can be transmitted by injecting drug use and sexual intercourse. Superinfection might have incidence rates comparable to those of initial HIV infection. Clinicians should encourage safe sexual and injecting drug use practices for HIV-infected patients because superinfection has detrimental effects on clinical outcomes and could pose a concern for large-scale antiretroviral treatment plans. The occurrence of superinfection has implications for vaccine research, since it seems initial HIV infection is not fully protective against a subsequent infection. Additional collaborative research could benefit care of patients and inform future vaccine design.
Obesity and the lung: 4 {middle dot} Obesity and asthma
Authors: D D Sin, E R Sutherland
Journal: Thorax (2008)

Over the past 30 years there has been an epidemic of both obesity and asthma in the western world. A large body of robust epidemiological data has linked obesity with the development and severity of asthma in both children and adults and weight reduction with improvements in asthma severity and symptoms. However, it remains unsettled whether this relationship is causal or confounded by some other factor(s) as mechanistic and physiological studies have produced heterogeneous and at times conflicting findings. This review examines the clinical and epidemiological relationship between obesity and asthma and the purported mechanisms that may link these two processes together.
Reviews and Notes: Hematology: Sickle Cell Disease; and Sickle Cell Disease: Pathophysiology, Diagnosis, and Management
Authors: Daniel Brookoff
Journal: Annals of Internal Medicine (1994)

Literature of Medicine15 January 1994Reviews and Notes: Hematology: Sickle Cell Disease; and Sickle Cell Disease: Pathophysiology, Diagnosis, and ManagementDaniel Brookoff, MDDaniel Brookoff, MDUniversity of Tennessee College of Medicine, Memphis, TN 38103Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-120-2-199401150-00035 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Sickle Cell DiseaseSecond edition. Graham R. Serjeant. 631 pages. Oxford: Oxford University Press; 1992. $59.00.Sickle Cell Disease: Pathophysiology, Diagnosis, and ManagementVipul N. Mankad and R. Blaine Moore; eds. Westport, Connecticut: Praeger; 1992. $79.95.Sickle cell disease has been both a triumph and a tragedy for American medicine. Scientific investigations into sickle cell disease ushered in the age of molecular medicine. At the same time, the history of sickle cell disease is also remarkable for the thousands of American children who, over the course of 300 years, died without notice from a disease that remained “undiscovered.” The paradox ... Author, Article, and Disclosure InformationAffiliations: University of Tennessee College of Medicine, Memphis, TN 38103 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 15 January 1994Volume 120, Issue 2Page: 174KeywordsAnatomical pathologyBlood cellsClinical pathologyGenetic diseasesHematology and oncologyHemoglobinMolecular biologyPatientsResearch laboratoriesSickle cell disease Issue Published: 15 January 1994 Copyright & PermissionsCopyright © 1994 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Efficacy and Safety of Abatacept in Lupus Nephritis: A Twelve‐Month, Randomized, Double‐Blind Study
Authors: Richard Furie, Kathy Nicholls, Tien‐Tsai Cheng, Frederic Houssiau, Ruben Burgos‐Vargas, Shun‐Le Chen, Jan L. Hillson, Stephanie Meadows‐Shropshire, Michael Kinaszczuk, Joan T. Merrill
Journal: Arthritis & Rheumatology (2013)

To compare the efficacy and safety of intravenous (IV) abatacept, a selective T cell costimulation modulator, versus placebo for the treatment of active class III or IV lupus nephritis, when used on a background of mycophenolate mofetil and glucocorticoids.This was a 12-month, randomized, phase II/III, multicenter, international, double-blind study. A total of 298 patients were treated in 1 of 3 IV treatment arms: placebo, abatacept at the standard weight-tiered dose (approximating 10 mg/kg), or abatacept at 30 mg/kg for 3 months, followed by the standard weight-tiered dose (abatacept 30/10). The primary end point, time to confirmed complete response, was a composite measure that required maintenance of glomerular filtration rate, minimal proteinuria, and inactive urinary sediment over the 52-week treatment period.There were no differences among treatment arms in the time to confirmed complete response or in the proportion of subjects with confirmed complete response following 52 weeks of treatment. Treatment with abatacept was associated with greater improvements from baseline in anti-double-stranded DNA antibody, C3, and C4 levels. Among 122 patients with nephrotic-range proteinuria, treatment with abatacept resulted in an ∼20-30% greater reduction in mean urinary protein-to-creatinine ratio compared with placebo. Abatacept was well tolerated; rates of deaths, serious adverse events, and serious infections were similar across treatment arms. Gastroenteritis and herpes zoster occurred more frequently with abatacept treatment.Although the primary end point was not met, abatacept showed evidence of biologic activity and was well tolerated in patients with active class III or IV lupus nephritis.
Effect of Oral Anticoagulant (Marcumar) on Prothrombin and Related Components in Blood Coagulation
Authors: SHIRLEY A. JOHNSON, M. JUNE CALDWELL, EDWARD MCCALL PRIEST
Journal: Circulation Research (1957)

Marcumar has been considered as an excellent anticoagulant for long term management. It was found that the effect of the drug on plasma levels of prothrombin and autoprothrombin I and autoprothrombin II differed from that of the drugs previously studied using the technics described. Autoprothrombin II was not reduced by Marcumar. This clotting factor, autoprothrombin II, has been found to have no influence on the Quick prothrombin time which is the test generally used to follow the effect of anticoagulants on the clotting mechanisms. The two coagulation factors which were found to decrease following the administration of Marcumar, prothrombin and autoprothrombin I, both influence the Quick prothrombin time.
The effect of a bioactive collagen membrane releasing PDGF or GDF-5 on bone regeneration
Authors: Seiichi Yamano, Ken Haku, Takuto Yamanaka, Jisen Dai, Tadahiro Takayama, Ryutaro Shohara, Keita Tachi, Mika Ishioka, Shigeru Hanatani, Sanjay Karunagaran, Keisuke Wada, Amr M Moursi
Journal: Biomaterials (2014)
Velcro crackles: the key for early diagnosis of idiopathic pulmonary fibrosis?
Authors: Vincent Cottin, Jean-François Cordier
Journal: European Respiratory Journal (2012)

Idiopathic pulmonary fibrosis (IPF), affecting individuals mostly aged 60–70 yrs, is the most common and the most severe of idiopathic interstitial pneumonias, with a median survival of only 3 yrs. The incidence and mortality of IPF has risen dramatically in the last decade [1]. Furthermore, IPF is one of the most challenging diseases for therapy developments, due to its complex and unresolved pathogenic processes, the possible inadequate drug diffusion in fibrotic lungs, and difficulties in designing clinical trials [2]. Up until now, no treatment could prevent the relentless progression of IPF to end-stage lung and ensuing death. However, drug therapy in IPF has recently regained hope with the publication of clinical trials using pirfenidone or the triple tyrosine kinase inhibitor BIBF 1120 that demonstrated an effect in limiting the decline in lung function [3–5].

Given these therapeutic advances, diagnosing IPF at an earlier stage becomes a relevant healthcare issue. Indeed, pirfenidone has been approved in Japan and in the European Union, and is indicated in mild-to-moderate IPF, which in the absence of a consensus definition may correspond to patients with forced vital capacity (FVC) >50% predicted and diffusing capacity of the lung for carbon monoxide ( D L,CO) >35% pred ( i.e. pulmonary function inclusion criteria for the recent phase III pirfenidone trials) [3]. Similarly, in a phase II study, BIBF 1120 has demonstrated a trend toward a reduction in lung function decline in patients with FVC >50% pred and D L,CO >30% pred [4], and is currently evaluated in a phase III study (clinical trial identifier number NCT01335464). The criteria chosen for these trials …
Mitochondrial Integrity and Function in Atherogenesis
Authors: Scott W. Ballinger, Cam Patterson, Cynthia A. Knight-Lozano, David L. Burow, Caryl A. Conklin, Zhaoyong Hu, Johannes Reuf, Chris Horaist, Russell Lebovitz, Glenn C. Hunter, Ken McIntyre, Marschall S. Runge
Journal: Circulation (2002)

Coronary atherosclerotic disease remains the leading cause of death in the Western world. Although the exact sequence of events in this process is controversial, reactive oxygen and nitrogen species (RS) likely play an important role in vascular cell dysfunction and atherogenesis. Oxidative damage to the mitochondrial genome with resultant mitochondrial dysfunction is an important consequence of increased intracellular RS.We examined the contribution of mitochondrial oxidant generation and DNA damage to the progression of atherosclerotic lesions in human arterial specimens and atherosclerosis-prone mice. Mitochondrial DNA damage not only correlated with the extent of atherosclerosis in human specimens and aortas from apolipoprotein E(-/-) mice but also preceded atherogenesis in young apolipoprotein E(-/-) mice. Apolipoprotein E(-/-) mice deficient in manganese superoxide dismutase, a mitochondrial antioxidant enzyme, exhibited early increases in mitochondrial DNA damage and a phenotype of accelerated atherogenesis at arterial branch points.Mitochondrial DNA damage may result from RS production in vascular tissues and may in turn be an early event in the initiation of atherosclerotic lesions.
THE DISCOVERY OF THE APPLICATION OF ETHER AND OTHER VAPOURS TO SURGERY.
Authors: H. Bennet, Horace Wells, ThomasWm. Kennedy, P.B. Mignault, CincinnatusA. Taft, JohnC. Warren, DanelT. Curtis, S. Fuller, P.W. Ellsworth, E. Marcy, G.B. Hawley, JohnM. Riggs, Mylo Lee, F.C. Goodrich, J. Gaylord Wells, WmH. Burleigh, S. Fuller, George Summer, Benj. Rogers, L.B. Beresford, H. Allew Grant, Wm.James Barry, E.E. Marcy, C.A. Taft, DavisS. Dodge, P.W. Ellsworth, GordonW. Russell, G.P. Hawley, E.R. Hunt, David Crary, John Schue, Henry Lee
Journal: The Lancet (1847)
Preoperative Uracil, Tegafur, and Concomitant Radiotherapy in Operable Rectal Cancer: A Phase II Multicenter Study With 3 Years' Follow-Up
Authors: Carlos Fernández-Martos, Jorge Aparicio, Carles Bosch, Marilo Torregrosa, Juan Manuel Campos, Salvador Garcera, Jose Maria Vicent, Inmaculada Maestu, Miguel Angel Climent, Jose Luis Mengual, Alejandro Tormo, Ana Hernandez, Rafael Estevan, Jose Maria Richart, Vicente Viciano, Natalia Uribe, Jorge Campos, Ramon Puchades, Francisco Arlandis, Daniel Almenar
Journal: Journal of Clinical Oncology (2004)

Purpose To assess tolerance and efficacy of preoperative treatment with uracil/tegafur and radiotherapy (RT) followed by surgery and postoperative flurouracil (FU)/leucovorin (LV) in patients with rectal cancer. Patients and Methods Patients (n = 94) with potentially resectable tumors, ultrasound at stages T2N+ (n = 4), T3 (n = 77), T4 (n = 13) were treated with UFT (400 mg/m 2 /d, 5 days a week for 5 weeks) and concomitant RT to the pelvis (45 Gy; 1.8 Gy/d over 5 weeks). Patients underwent surgery 5 to 6 weeks later followed by four cycles of FU/LV. Primary end points included downstaging, pathologic responses, and sphincter-preserving surgery. Secondary end points were recurrence-free survival and overall survival. Results All patients received the full RT dose. Fifteen patients (16%) needed UFT dose reduction. Preoperative G3+ toxicities included diarrhea (14%), leukopenia (1%), thrombocytopenia (1%), and nausea (4%). The downstaging rate was 54%, pathologic complete response (pCR) was 9% and, in an additional 23%, there were only residual microscopic foci. When cellular viability criteria were taken into account, the pCR was 15%. From 43 patients with abdominoperineal resection indication, 11 (25%) had sphincter-preserving surgery performed. Postoperative scheduled chemotherapy dose was not administered to 24% of patients because of G3+ toxicity (diarrhea, 8%; mucositis, 9%; and leukopenia, 7%). Patients with downstaging had significantly higher survival and recurrence-free survival rates than those without. At 3 years, actuarial patterns of failure were pelvic, 5% and distant, 11%. OS was 75%. Conclusion UFT combined with RT is safe and effective. In resectable rectal cancer, if preoperative treatment is considered, this approach can be an option.
Goodpasture's syndrome with normal renal function
Authors: P Carre, JJ Lloveras, A Didier, B Gorguet, C Orfila, D Durand, P Leophonte
Journal: European Respiratory Journal (1989)

Two cases of Goodpasture's syndrome with severe pulmonary haemorrhage and normal renal function are described. In spite of minor (patient 2) or even no (patient 1) biological or light microscopic signs of glomerulonephritis, immunofluorescence of immunoglobulin G (IgG) was strongly positive in a linear fashion along the glomerular basement membranes in both patients. We suggest that renal biopsy in patients with apparently idiopathic pulmonary haemorrhage may lead to an early diagnosis of Goodpasture's syndrome. It is not possible in this disease to recognize on presentation those patients who will remit spontaneously and those who will undergo severe disease. The deadly evolution for patient 1 and some cases in the literature lend support to the notion that cytostatics and plasma exchange must be added to corticosteroids, even if pulmonary haemorrhage is not active and renal function is normal at the time.
Targeting Multiple Kinase Pathways: A Change In Paradigm
Authors: Lucy Gossage, Tim Eisen
Journal: Clinical Cancer Research (2010)

Abstract Anticancer drugs that target protein kinases include small molecule inhibitors and monoclonal antibodies. Feedback loops and cross talk between signaling pathways impact significantly on the efficacy of cancer therapeutics, and resistance to targeted agents is a major barrier to effective treatments. Increasingly, therapies are being designed to target multiple kinase pathways. This can be achieved using a single agent that inhibits multiple signaling pathways or a combination of highly selective agents. In this review we discuss the principles of specifically targeting multiple kinase pathways with particular reference to angiogenic signaling pathways. Clin Cancer Res; 16(7); 1973–8. ©2010 AACR.
Concurrent Hyperfractionated Radiotherapy and Low-Dose Daily Carboplatin/Paclitaxel in Patients With Early-Stage (I/II) Non–Small-Cell Lung Cancer: Long-Term Results of a Phase II Study
Authors: Branislav Jeremić, Biljana Milicić, Ljubisa Acimović, Slobodan Milisavljević
Journal: Journal of Clinical Oncology (2005)

Purpose Feasibility and activity of concurrent hyperfractionated radiotherapy (Hfx RT) and low-dose, daily carboplatin and paclitaxel were investigated in patients with early-stage (I/II) non–small-cell lung cancer in a phase II study. Patients and Methods Fifty-six patients started their treatment on day 1 with 30 mg/m 2 of paclitaxel. Hfx RT using 1.3 Gy bid to a total dose of 67.6 Gy and concurrent low-dose daily carboplatin 25 mg/m 2 and paclitaxel 10 mg/m 2 , both given Mondays through Fridays during the RT course, started from the second day. Results There were 29 complete responses (52%) and 15 partial responses (27%), and 12 patients (21%), experienced stable disease. The median survival time was 35 months, and 3- and 5-year survival rates were 50% and 36%, respectively. The median time to local progression has not been achieved, but 3- and 5-year local progression-free survival rates were 56% and 54%, respectively. The median time to distant metastasis has not been achieved, but 3- and 5- year distant metastasis-free survival rates were 61% and 61%, respectively. The median and 5-year cause-specific survivals were 39 months and 43%, respectively. Acute high-grade (&gt; 3) toxicity was hematologic (22%), esophageal (7%), or bronchopulmonary (7%). No grade 5 toxicity was observed. Late high-grade toxicity was rarely observed (total, 10%). Conclusion Hfx RT and concurrent low-dose daily carboplatin/paclitaxel was feasible with low toxicity and effective in patients with stage I/II non–small-cell lung cancer. It should continue to be investigated for this disease.