tbuckley/cabot-search huggingface dataset:
Acceleration of Crossbridge Kinetics by Protein Kinase A Phosphorylation of Cardiac Myosin Binding Protein C Modulates Cardiac Function
Authors: Carl W. Tong, Julian E. Stelzer, Marion L. Greaser, Patricia A. Powers, Richard L. Moss
Journal: Circulation Research (2008)

Normal cardiac function requires dynamic modulation of contraction. beta1-adrenergic-induced protein kinase (PK)A phosphorylation of cardiac myosin binding protein (cMyBP)-C may regulate crossbridge kinetics to modulate contraction. We tested this idea with mechanical measurements and echocardiography in a mouse model lacking 3 PKA sites on cMyBP-C, ie, cMyBP-C(t3SA). We developed the model by transgenic expression of mutant cMyBP-C with Ser-to-Ala mutations on the cMyBP-C knockout background. Western blots, immunofluorescence, and in vitro phosphorylation combined to show that non-PKA-phosphorylatable cMyBP-C expressed at 74% compared to normal wild-type (WT) and was correctly positioned in the sarcomeres. Similar expression of WT cMyBP-C at 72% served as control, ie, cMyBP-C(tWT). Skinned myocardium responded to stretch with an immediate increase in force, followed by a transient relaxation of force and finally a delayed development of force, ie, stretch activation. The rate constants of relaxation, k(rel) (s-1), and delayed force development, k(df) (s-1), in the stretch activation response are indicators of crossbridge cycling kinetics. cMyBP-C(t3SA) myocardium had baseline k(rel) and k(df) similar to WT myocardium, but, unlike WT, k(rel) and k(df) were not accelerated by PKA treatment. Reduced dobutamine augmentation of systolic function in cMyBP-C(t3SA) hearts during echocardiography corroborated the stretch activation findings. Furthermore, cMyBP-C(t3SA) hearts exhibited basal echocardiographic findings of systolic dysfunction, diastolic dysfunction, and hypertrophy. Conversely, cMyBP-C(tWT) hearts performed similar to WT. Thus, PKA phosphorylation of cMyBP-C accelerates crossbridge kinetics and loss of this regulation leads to cardiac dysfunction.
Towards prognostic biomarkers in pulmonary arterial hypertension
Authors: J-L. Cracowski
Journal: European Respiratory Journal (2012)

The most reliable way to assess the clinical impact of a therapeutic intervention in pulmonary arterial hypertension (PAH) is through its effect on well-defined clinical end-points, such as mortality. However, this standard is often impractical because of the long period and large number of patients required to reach these clinical end-points, and substitutes, such as the 6-min walking distance, are often used. Biomarkers may also be reliable substitutes for clinical end-points, and are called surrogate end-points when they meet such requirements. According to the US National Institutes of Health Biomarkers Definitions Working Group, a biomarker is “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” [1]. However, while this definition is used for drug discovery, another narrower definition is still commonly used: “disease-associated molecular changes in body tissue and fluids”, i.e. a biological marker [2]. Among the estimated 150,000 papers documenting thousands of biological markers, less than 100 biomarkers are routinely used in the clinic [2]. In the field of PAH, which is a rare disease, most biomarker studies examined less than 100 patients, and therefore lacked the statistical power needed to demonstrate a strong association between any biomarker and death. Registries such as the Registry to Evaluate Early And Long-term PAH Disease Management (REVEAL) [3] have the advantage of enabling the study of larger populations and, therefore, have much better statistical power. However, in most cases, registries are not designed to evaluate new biomarkers, as they do not reach the necessary quality of biological sampling with storage of samples in a biobank, and are often a mix of incident and prevalent patients. In addition, many studies have focused on just one biomarker, while there is increasing …
Marathoner DeMar: Physiological Studies2
Authors: D. B. Dill
Journal: JNCI Journal of the National Cancer Institute (1965)

Clarence DeMar competed in more than 1,000 distance races, including 32 of the Boston Athletic Association Marathons. His performance in those marathons was best in his fourth decade and declined thereafter. However, even in his last, at age 66, he ran at 177 meters per minute or 7 miles per hour for almost 4 hours. This surpasses the capability of most young men. Laboratory studies revealed exceptionally superior cardiovascular and respiratory systems with a low basal heart rate, low blood pressure, and large vital capacity. Hemoglobin concentration and other properties of the blood were not unusual. His maximal attainable rate of oxygen consumption, an over-all measure of fitness, was 60 ml per minute-kg at age 49, the highest we have observed at that age.
The Accessory Optic System
Authors: J I Simpson
Journal: Annual Review of Neuroscience (1984)

Despite its name, the accessory optic system (AOS) is a primary visual system. Not only do retinal ganglion cell axons constitute a major input to AOS nuclei, but the AOS contributes fundamentally to retinal image stabilization, which is important for the proper functioning of other visual systems. Although the AOS has been recognized anatomically for well over 100 years and is present in all vertebrate classes (Mai 1978), the first physiological studies were not reported until 1959 (Marg et al 1959). Until quite recently, progress in understanding AOS physiology was limited. Indeed, in the most recent review of the physiol­ ogy of the AOS, Marg (1973) expressed concern as to whether the AOS even had a normal function. In the intervening years substantial progress has been made in revealing both the anatomy and physiology of the AOS, and these advances are the focus of this review. After a brief survey of the gross anatomical features of the AOS, the following topics are treated: retinal ganglion cell morphology and distribution, efferents and nonvisual afferents of the AOS, visual response properties of AOS neurons and their interpretation, behavioral consequences of AOS lesions, and relations and comparisons be­ tween the AOS and an allied pretectal nucleus.
Pancrustacean Phylogeny in the Light of New Phylogenomic Data: Support for Remipedia as the Possible Sister Group of Hexapoda
Authors: B. M. von Reumont, R. A. Jenner, M. A. Wills, E. Dell'Ampio, G. Pass, I. Ebersberger, B. Meyer, S. Koenemann, T. M. Iliffe, A. Stamatakis, O. Niehuis, K. Meusemann, B. Misof
Journal: Molecular Biology and Evolution (2011)

Remipedes are a small and enigmatic group of crustaceans, first described only 30 years ago. Analyses of both morphological and molecular data have recently suggested a close relationship between Remipedia and Hexapoda. If true, the remipedes occupy an important position in pancrustacean evolution and may be pivotal for understanding the evolutionary history of crustaceans and hexapods. However, it is important to test this hypothesis using new data and new types of analytical approaches. Here, we assembled a phylogenomic data set of 131 taxa, incorporating newly generated 454 expressed sequence tag (EST) data from six species of crustaceans, representing five lineages (Remipedia, Laevicaudata, Spinicaudata, Ostracoda, and Malacostraca). This data set includes all crustacean species for which EST data are available (46 species), and our largest alignment encompasses 866,479 amino acid positions and 1,886 genes. A series of phylogenomic analyses was performed to evaluate pancrustacean relationships. We significantly improved the quality of our data for predicting putative orthologous genes and for generating data subsets by matrix reduction procedures, thereby improving the signal to noise ratio in the data. Eight different data sets were constructed, representing various combinations of orthologous genes, data subsets, and taxa. Our results demonstrate that the different ways to compile an initial data set of core orthologs and the selection of data subsets by matrix reduction can have marked effects on the reconstructed phylogenetic trees. Nonetheless, all eight data sets strongly support Pancrustacea with Remipedia as the sister group to Hexapoda. This is the first time that a sister group relationship of Remipedia and Hexapoda has been inferred using a comprehensive phylogenomic data set that is based on EST data. We also show that selecting data subsets with increased overall signal can help to identify and prevent artifacts in phylogenetic analyses.
Britain could still have a comprehensive NHS without rationing
Authors: K. MacKay
Journal: BMJ (1996)

EDITOR,—I find it difficult to agree with Richard Smith in his editorial on rationing health care.1 To assert that some form of rationing or “denial of potentially beneficial treatment” has always been present in the NHS is surely not a justification for its existence.

There is a quantitative and qualitative difference between having to wait 4-6 months for a hernia repair and waiting 12-24 months. When it becomes impossible to find a bed for an emergency admission and patients …
Phospholipase A2 augments contraction and intracellular calcium mobilization through thromboxane A2 in bovine tracheal smooth muscle
Authors: Y. Takata, Y. Nishimura, H Maeda, M Yokoyama
Journal: European Respiratory Journal (1999)

Phospholipase A2 (PLA2) induces hyper-sensitivity to muscarinic agonists in airway smooth muscle in vitro. The precise mechanism of this is unknown, but might involve altered calcium homeostasis. In order to elucidate the effects of PLA2, on bovine tracheal smooth muscle contraction, isometric tension and intracellular calcium concentration ([Ca2+]i) were simultaneously measured in fura 2-loaded muscle strips. A high concentration of PLA2 (0.5 microg x mL(-1)) caused the muscle strips to contract, and this contractile response was significantly attenuated by pretreatment with indomethacin (IND; 10 microM), but not by nordihydroguaiaretic acid (NDGA; 10 microM). A low concentration of PLA2 (0.02 microg x mL(-1)) did not directly contract muscle strips. However a low concentration PLA2 significantly enhanced the threshold of the contractile response and that of the [Ca2+]i response to acetylcholine (ACh), but not that of the response to a high K+ concentration. These augmented responses to ACh returned to control levels after pretreatment with IND, a thromboxane (TX) synthetase inhibitor (OKY-046; 10 microM) or a TXA2 receptor antagonist (ONO-3708; 10 microM), but not after NDGA pretreatment. These results suggest that a low concentration of phospholipase A2 enhances smooth muscle responsiveness to acetylcholine by agonist-mediated Ca2+ mobilization facilitated by thromboxane A2. It is concluded that phospholipase A2 plays an important role in bronchial hypersensitivity involving thromboxane A2. It remains to be examined whether similar abnormalities in calcium homeostasis and muscarinic receptor function or coupling are involved in the pathogenesis of asthma.
Effects of Alkalosis on Plasma Concentration and Urinary Excretion of Inorganic Phosphate in Man*
Authors: Marvous E. Mostellar, Elbert P. Tuttle
Journal: Journal of Clinical Investigation (1964)

In 1924, Haldane, Wigglesworth, and Wood- row reported on the effect of reaction changes on human inorganic metabolism (1).They found that respiratory alkalosis caused a sharp fall and respiratory acidosis a sharp rise in serum phos- phorus concentration.They also examined metabolic changes induced by oral ingestion of Na- HCO3 or NH4Cl for several days, but respiratory compensation would have minimized pH changes under the conditions of their experiments.They found no significant deviation of serum phosphorus from normal values.The influence of alkalosis on serum and urinary phosphorus has been intermittently observed since that time during ex- periments on hydrogen ion disturbances in dogs and in man (2-9).However, most recent re- views on phosphorus metabolism and the para- thyroids do not mention the effect of blood hy- drogen ion concentration or carbon dioxide tension upon the concentration of phosphorus in the serum or upon the urinary excretion and clearance of phosphorus (10-22).Our study was undertaken to evaluate the range of variation of plasma phosphorus concentration under the influence of elevated blood pH, to as- certain whether hydrogen ion concentration or CO2 content is the critical determinant, and to consider possible explanations for the fall in con- centration of phosphorus.
The place of comorbidities in ‘COPD control panel’
Authors: Ivan Ivanovich Vishnivetsky, Oleksandr Dyadyk, Yuriy Mostovoy
Journal: Thorax (2013)

We read with interest about the new chronic obstructive pulmonary disease (COPD) care framework proposed by Agusti and MacNee.1 The ‘control panel’ idea is very interesting and useful because it allows keeping in mind all we need for making optimal treatment decisions. But this aircraft cockpit metaphor reminded us that current evidence-based guidelines resemble the flight simulator rather than the real plane. In our everyday practice we base our decisions on the ‘dummy’ evidence derived from purified non-representative cohorts of COPD patients.2 Examples are Body mass index, airflow Obstruction, Dyspnea, and Exercise …
Tumor Characteristics Associated With Mammographic Detection of Breast Cancer in the Ontario Breast Screening Program
Authors: V. A. Kirsh, A. M. Chiarelli, S. A. Edwards, F. P. O'Malley, R. S. Shumak, M. J. Yaffe, N. F. Boyd
Journal: JNCI Journal of the National Cancer Institute (2011)

Few studies have compared the prognostic value of tumor characteristics by type of breast cancer diagnosed in the interval between mammographic screenings with screen-detected breast cancers. We conducted a case–case study within the cohort of women (n = 431 480) in the Ontario Breast Screening Program who were aged 50 years and older and were screened between January 1, 1994, and December 31, 2002. Interval cancers , defined as breast cancers diagnosed within 24 months after a negative screening mammogram, were designated as true interval cancers (n = 288) or missed interval cancers (n = 87) if they were not identified at the time of screening but were identified in retrospect. Screen-detected breast cancers (n = 450) were selected to match interval cancers. Tumors were evaluated for stage, grade, mitotic index, histology, and expression of hormone receptors and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by conditional logistic regression. Both true and missed interval cancers were of higher stage and grade than matched screen-detected breast cancers. However, true interval cancers had a higher mitotic index (OR = 3.13, 95% CI = 1.81 to 5.42), a higher percentage of nonductal histology (OR = 1.94, 95% CI = 1.05 to 3.59), and were more likely to be both estrogen receptor–negative (OR = 2.09, 95% CI = 1.32 to 3.30) and progesterone receptor–negative (OR = 2.49, 95% CI = 1.68 to 3.70) compared with matched screen-detected tumors. In this study, interval cancers were of higher stage and grade compared with screen-detected cancers. True interval cancers were more likely to have additional adverse prognostic features of estrogen and progesterone receptor negativity and nonductal morphology. The findings suggest a need for more sensitive screening modalities to detect true interval breast cancers and different approaches for early detection of fast-growing tumors.
Rotational Atherectomy Does Not Reduce Recurrent In-Stent Restenosis
Authors: Juergen vom Dahl, Ulrich Dietz, Philipp K. Haager, Sigmund Silber, Luigi Niccoli, Hans Juergen Buettner, Francois Schiele, Martyn Thomas, Philippe Commeau, David R. Ramsdale, Eulogio Garcia, Christian W. Hamm, Rainer Hoffmann, Thorsten Reineke, Heinrich G. Klues
Journal: Circulation (2002)

Aim of this trial was to compare rotational atherectomy followed by balloon angioplasty (rotablation [ROTA] group) with balloon angioplasty (percutaneous transluminal coronary angioplasty [PTCA] group) alone in patients with diffuse in-stent restenosis.The ARTIST study is a multicenter, randomized, prospective European trial with 298 patients with in-stent restenosis>70% (mean lesion length, 14 +/- 8 mm) in stents, implanted in coronary arteries for >/= 3 months. In the PTCA group, angioplasty was performed at the discretion of the local investigator, and rotablation was performed by using a stepped-burr approach followed by adjunctive PTCA with low (</= 6 atm) inflation pressure. Intravascular ultrasound during the intervention and at follow-up was used in a substudy in 86 patients (45 PTCA, 41 ROTA). Angiography demonstrated no difference regarding the short-term outcome, with equivalent procedural success rates defined as remaining stenosis <30% (89% PTCA, 88% ROTA). However, the results showed that, in the long term, PTCA was a significantly better strategy than ROTA. Mean net gain in minimal lumen diameter was 0.67 mm and 0.45 mm for PTCA and ROTA, respectively (P=0.0019). Mean gain in diameter stenosis was 25% and 17% (P=0.002), resulting in restenosis (>/= 50%) rates of 51% (PTCA) and 65% (ROTA) (P=0.039). By intravascular ultrasound, the major difference was the missing stent over-expansion during PTCA after ROTA. Six-month event-free survival was significantly higher after PTCA (91.3%) compared with ROTA (79.6%, P=0.0052).In terms of the primary objective of the study, PTCA produced a significantly better long-term outcome than ROTA followed by adjunctive low-pressure PTCA.
Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma
Authors: David Semela, Anne-Christine Piguet, Mirjam Kolev, Karin Schmitter, Ruslan Hlushchuk, Valentin Djonov, Christoforos Stoupis, Jean-François Dufour
Journal: Journal of Hepatology (2007)
Biological treatment of rheumatoid arthritis: towards a more cost-effective re-treatment regimen using rituximab?
Authors: M J H Boumans, K Vos, D M Gerlag, P P Tak
Journal: Annals of the Rheumatic Diseases (2011)

We would like to share ideas on the report on “Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the Need for Clinical Trials [1].”Balevic noted that “<i>well-designed clinical trials that include patients with rheumatic disease are urgently needed to characterize the efficacy, safety, and target exposures for hydroxychloroquine</i> [1].”
Dasatinib-Responsive Mast Cell Neoplasms As Initial Presentation of Chronic Myelogenous Leukemia in Blast Phase
Authors: Carlos E. Vigil, Sa A. Wang, Jorge E. Cortes, Carlos Bueso-Ramos, Srdan Verstovsek, Roman Shinder, Su S. Chen, Ruth L. Katz, Abha Khanna, Bita Esmaeli, John T. Manning, M. James You, Roberto N. Miranda
Journal: Journal of Clinical Oncology (2011)

A 50-year-old man presented with a 3-month history of left supraorbital mass, left leg pain, and walking difficulty; he denied symptoms of flushes, diarrhea, or syncope.On physical examination, the patient had a 2-cm firm, nontender mass centered at the junction of the left lateral and superior orbital walls.Patient did not have lymphadenopathy or organomegaly.The patient was a 30 pack per year smoker, and his medical history was not relevant.On admission, his WBC count was 8.7 ϫ 10 9 /L; hemoglobin, 11.7 g/dL; and platelets, 370 ϫ 10 9 /L.A peripheral blood cell differential was normal.Lactate dehydrogenase was normal, and tryptase level was slightly increased at 12.8 ng/dL.Radiologic studies revealed a lytic lesion involving the superior and lateral orbital walls (Fig 1), multiple lytic lesions in the left pelvis and left scapula, and a pathologic fracture of the left femoral head.Biopsies of the orbit, left femoral head lesion, and random iliac crest bone marrow were performed.Pathologic and cytogenetic findings.Excision of the left orbital mass showed an atypical mononuclear cell infiltrate with abundant eosinophils.The mononuclear cells showed scant to moderate cytoplasm with pale, coarse basophilic granules, which were better appreciated on a significant proportion of cells on touch imprints (Fig 2).These cells were strongly positive for CD117 and weakly positive for tryptase; approximately 15% were CD34ϩ.Biopsy of the left femur pathologic fracture revealed sheets of mononuclear cells, with focal tumor necrosis and stromal fibrosis.Similar to the mononuclear cells in the supraorbital mass, the mononuclear cells of the left femur contained basophilic and azurophilic granules, but the nuclei in the femur were oval to bilobed.Compared with the mononuclear cells of the orbital mass, the mononuclear cells of the femur were not only strongly positive for CD117 but also strongly positive for tryptase and negative for CD34.
Secretion of blood group substances in duodenal, gastric and stomal ulcer, gastric carcinoma, and diabetes mellitus
Authors: R. Doll, H. Drane, A. C. Newell
Journal: Gut (1961)

The ABO blood group and ABH secretor status have been determined for 368 patients with a duodenal ulcer, 202 patients with a gastric ulcer, 83 patients with a stomal ulcer, 105 patients with gastric cancer, 102 patients with diabetes mellitus, and a control group of 610 subjects consisting of healthy persons and of patients with other conditions attending the same hospital. The results have been analysed in conjunction with those reported in two other large series. For duodenal ulcer the results show that the relative incidence among non-secretors compared with secretors is 1.80 to 1, with 95% confidence limits of 1.55 to 1 and 2.03 to 1. For gastric ulcer the relative incidence is 1.42 to 1, with 95% confidence limits of 1.16 to 1 and 1.74 to 1. Comparison of the results for the two types of peptic ulcer shows that they are significantly different from one another. For both types of ulcer, the estimated risk among non-secretors was similar for blood group O and for the other blood groups and the results suggest that the specific risks associated with blood group O and with non-secretion multiply one another. It is concluded that the mechanisms by which blood group O and non-secretion affect the risk of developing a gastric or duodenal ulcer are related to one another; but that they do not depend on the presence of the blood group substances in the secretions. The proportion of non-secretors among patients with a stomal ulcer (49%) was higher than among patients with a duodenal ulcer (37%) and the order of the relationship between non-secretion and the three types of peptic ulcer (stomal, duodenal, and gastric) was the same as that for blood group O. Other data suggest that there may be a slight increase in the risk of gastric cancer among non-secretors, but that the occurrence of diabetes mellitus is independent of ABH secretion.