tbuckley/cabot-search huggingface dataset:
Natural moisturizing factor components in the stratum corneum as biomarkers of filaggrin genotype: evaluation of minimally invasive methods
Authors: S. Kezic, A. Kammeyer, F. Calkoen, J.W. Fluhr, J.D. Bos
Journal: British Journal of Dermatology (2009)

The carriers of loss-of-function mutations in the filaggrin gene (FLG) have reduced levels of natural moisturizing factor (NMF) in the stratum corneum. The concentration of NMF components which are formed by filaggrin protein breakdown in the stratum corneum might therefore be useful as a biomarker of the FLG genotype. OBJECTIVES To investigate the feasibility of different sampling methods for the determination of two NMF components, 2-pyrrolidone-5-carboxylic acid (PCA) and urocanic acid (UCA), in the stratum corneum as biomarkers for the FLG genotype.PCA and UCA from the stratum corneum were sampled by using a tape stripping technique and an extraction technique using skin patches containing potassium hydroxide (KOH). The concentrations of PCA and UCA were measured by high-performance liquid chromatography. Eleven carriers of an FLG mutation and 10 individuals wild type for the two most common FLG mutations (R501X and R2447X) [corrected] were included in the study.The most significant difference between the FLG genotypes was found for PCA sampled by the tape stripping technique. The mean values of PCA obtained by the tape stripping technique were, respectively, 0.18, 0.50 and 1.64 mmol g(-1) protein in homozygous (or compound heterozygous), heterozygous and wild-type genotypes (P < 0.005 homozygous vs. heterozygous; P < 0.0001 heterozygous vs. wild type). The tape stripping technique showed less intrasubject variation compared with the KOH patches, in particular when the concentrations of UCA and PCA on the tape strips were normalized for protein amount.The concentration of PCA in the stratum corneum collected by tape stripping showed it to be a feasible biomarker of the FLG genotype.
Activation of Notch-1 signaling maintains the neoplastic phenotype in human Ras-transformed cells
Authors: Sanne Weijzen, Paola Rizzo, Mike Braid, Radhika Vaishnav, Suzanne M. Jonkheer, Andrei Zlobin, Barbara A. Osborne, Sridevi Gottipati, Jon C. Aster, William C. Hahn, Michael Rudolf, Kalliopi Siziopikou, W. Martin Kast, Lucio Miele
Journal: Nature Medicine (2002)
Care.data: how Northern Ireland is doing it
Authors: B. O'Brien
Journal: BMJ (2014)

McCartney’s feature article accurately describes the Northern Ireland Electronic Care Record (NIECR).1 The NIECR is for direct care purposes only. The robust access controls and audit trail in the NIECR give confidence to patients that their identifiable information will only be viewed by those providing direct care. Patients are asked for their explicit consent by health and care staff before staff access the patient’s record. …
Flow-Dependent Dilation Mediated by Endogenous Kinins Requires Angiotensin AT <sub>2</sub> Receptors
Authors: Sonia Bergaya, Rob H.P. Hilgers, Pierre Meneton, You Dong, May Bloch-Faure, Tadashi Inagami, François Alhenc-Gelas, Bernard I. Lévy, Chantal M. Boulanger
Journal: Circulation Research (2004)

The vascular kallikrein-kinin system contributes to about one third of flow-dependent dilation in mice carotid arteries, by activating bradykinin B2 receptors coupled to endothelial nitric oxide (NO) release. Because the bradykinin/NO pathway may mediate some of the effects of angiotensin II AT2 receptors, we examined the possible contribution of AT2 receptors to the kinin-dependent response to flow. Changes in outer diameter after increases in flow rate were evaluated in perfused arteries from wild-type animals (TK+/+) and in tissue kallikrein-deficient mice (TK-/-) in which the presence of AT2 receptor expression was verified. Saralasin, a nonselective angiotensin II receptor antagonist, impaired significantly flow-induced dilation in TK+/+, whereas it had no effect in TK-/- mice. In both groups, blockade of AT1 receptors with losartan or candesartan did not affect the response to flow. Inhibition of AT2 receptors with PD123319 reduced significantly flow-induced dilation in TK+/+ mice, but had no significant effect in TK-/- mice. Combining PD123319 with the bradykinin B2 receptor antagonist HOE-140 had no additional effect to AT2 receptor blockade alone in TK+/+ arteries. Flow-dependent-dilation was also impaired in AT2 receptor deficient mice (AT2-/-) when compared with wild-type littermates. Furthermore, HOE-140 significantly reduced the response to flow in the AT2+/+, but not in AT2-/- mice. In conclusion, this study demonstrates that the presence of functional AT2 receptors is necessary to observe the contribution of the vascular kinin-kallikrein system to flow-dependent dilation.
Current status of monophasic action potential recording: theories, measurements and interpretations
Authors: M Franz
Journal: Cardiovascular Research (1999)

Time for primary review 26 days. 

Monophasic action potentials (MAPs) are extracellularly recorded wave forms that, under optimal conditions, can reproduce the repolarization time course of transmembrane action potentials (TAPs) with high fidelity [1–3]. While TAP recordings require the impalement of an individual cardiac cell by a glass-microelectrode and therefore generally are limited to in vitro preparations, MAPs can be recorded from the endocardium and epicardium of the in situ beating heart, including that of human subjects. MAP recordings therefore are suitable for studying the characteristics of local myocardial electrophysiology, especially of repolarization, in the clinical setting. This has made MAP recordings an important bridge between basic and clinical electrophysiology in multiple areas of arrhythmia research [4].

Despite the growing use of the MAP recording method, there still is surprisingly little hard data on the exact mechanism by which MAPs are created and recorded. New methods for recording MAPs recently have been proposed, and new theories and models have been suggested to explain the mechanisms that underlie the genesis of the MAP signal. There have been attempts to record MAPs from sites within the myocardial wall, an effort spurred on by the discovery that mid-myocardial cells (M-cells) have different repolarization characteristics than either epicardial or endocardial cells [5], and these different characteristics have been found to be important for the development of torsade de pointes arrhythmias [6]. This article attempts to review the available information on the MAP genesis and its particular recording modes. It also highlights some important MAP quality criteria and guidelines for correct interpretation of MAPs and how to avoid artifacts. Last but not least, important differences between unipolar and bipolar recordings of both MAPs and conventional electrograms will be discussed, as they pertain to the fidelity and spatial resolution of these recordings. … 

* Tel.: +202-745-8398; fax: +202-745-8473; e-mail: mfranz@washington.va.gov
Vulnerability of pulmonary capillaries during severe exercise
Authors: J B West
Journal: British Journal of Sports Medicine (2006)

The pulmonary capillaries are vulnerable to mechanical failure during strenuous exercise

It is remarkable that it has taken so long to recognise how vulnerable the pulmonary capillaries are to mechanical failure during strenuous exercise. After all, the extreme thinness of the capillary wall was appreciated when the first electron micrographs were obtained by Low in 1952. We now know that the total area of the blood-gas barrier (BGB) in the human lung is 50–100 m2 and that for more than half of this enormous area the thickness is only 0.2–0.3 μm.1 The result is that during severe exercise when the pulmonary vascular pressures rise to high levels, the capillary wall stresses become extremely high approaching the breaking stress of collagen.2 It is not surprising therefore that changes in the integrity of the BGB occur under these conditions.

Perhaps investigators were initially misled by early data from cardiac catheterisation procedures which suggested …
DEMONSTRATION OF MOUSE ISOANTIGENS AT THE CELLULAR LEVEL BY THE FLUORESCENT ANTIBODY TECHNIQUE
Authors: Göran Möller
Journal: The Journal of Experimental Medicine (1961)

The fluorescent antibody technique has been applied for the demonstration of mouse isoantigens at the cellular level. Specific reactions were obtained by the indirect or "sandwich" technique with a variety of living normal and neoplastic cells. Isoantigens of the H-2 system and of other systems could be demonstrated as well and appeared to be localized at the cell membrane. As far as the H-2 system was concerned, the membrane localization could be confirmed on histological sections. Different types of non-specific staining reactions have been identified and described. Pinocytosis and cell injury led to such reactions that were morphologically distinguishable from the specific "ring" reaction and as far as pinocytosis is concerned, could be easily avoided by reducing the incubation time. In addition, a non-specific staining reaction morphologically indistinguishable from the specific "ring" reaction could be seen in a small proportion of bone marrow and lymph node cells but in no other cell type studied. The possible nature of this reaction is discussed.
Association between childhood asthma and ADHD symptoms in adolescence - a prospective population-based twin study
Authors: N. Mogensen, H. Larsson, C. Lundholm, C. Almqvist
Journal: Allergy (2011)

To cite this article: Mogensen N, Larsson H, Lundholm C, Almqvist C. Association between childhood asthma and ADHD symptoms in adolescence – a prospective population-based twin study. Allergy 2011; 66: 1224–1230. Abstract Background: Cross-sectional studies report a relationship between childhood asthma and attention-deficit hyperactivity disorder (ADHD) symptoms, but the mechanisms are yet unclear. Our objective was to investigate the longitudinal link between childhood asthma and the two dimensions of ADHD (hyperactivity–impulsivity, HI, and inattention, IN) in adolescence. We also aimed to explore the genetic and environmental contributions and the impact of asthma medication. Methods: Data on asthma, HI and IN, birth weight, socioeconomic status, zygosity, and medication were collected from the Swedish Medical Birth Register and through parental questionnaires at ages 8–9 and 13–14 years on 1480 Swedish twin pairs born 1985–1986. The association between asthma at age 8–9 and ADHD symptoms at age 13–14 was assessed with generalized estimating equations, and twin analyses to assess the genetic or environmental determinants were performed. Results: Children with asthma at age 8–9 had an almost twofold increased risk of having one or more symptom of HI (OR 1.88, 95% CI 1.18–3.00) and a more than twofold increased risk to have three symptoms or more of HI (OR 2.73, 95% CI 1.49–5.00) at age 13–14, independent of asthma medication. For IN, no significant relationship was seen. Results from twin modeling indicate that 68% of the phenotypic correlation between asthma and HI (r = 0.23, 0.04–0.37) was because of genetic influences. Conclusions: Our findings suggest that childhood asthma is associated with subsequent development of HI in early adolescence, which could be partly explained by genetic influences. Early strategies to identify children at risk may reduce burden of the disease in adolescence.
A COMPARATIVE STUDY OF THE GROWTH, NUTRITION, AND METABOLISM OF THE PRIMARY AND THE TRANSFORMED HUMAN CELLS IN VITRO
Authors: R. Shihman Chang
Journal: The Journal of Experimental Medicine (1961)

The growth characteristics, nutritional requirements, and metabolic activities of primary explants (chiefly amnion) and transformed human cells (derived from amnion, conjunctiva, and cervical cancer) were compared. Major differences observed are as follows: 1. Five types of human tissue when freshly explanted in vitro were found to have varying but limited growth potential in contrast to the autonomous and apparently unlimited growth of the transformed cell. 2. A requirement for an external source of inositol or glutamine could not be demonstrated for the slowly multiplying primary amnions in contrast to the rapidly growing transformed cells which degenerated in the absence of either metabolite. 3. Unlike the transformed cells, the primary amnion cells fixed an insignificant amount of CO(2); when infected by the Coxsackie virus, however, a requirement for CO(2) in the formation of more virus became readily demonstrable. 4. The biggest difference in the incorporation of various C(14) substrates occurred in the nucleic acid fractions. 5. The difference in the incorporation of glycine into the protein fraction was very small. 6. The utilization of glucose, ribose, and xylose as well as the oxidation of lactic acid into CO(2) by the primary amnion cells occurred at a rate much lower than that of the transformed cells. 7. The cytotoxic dose of 5-fluorodeoxyuridine for the primary amnion was at least 100 times that of the transformed cells although growth inhibition was readily demonstrated at 0.1 microg. per ml. for both types of cells. Based on these observations, several hypotheses are put forth for consideration.
Sildenafil and B-Type Natriuretic Peptide Acutely Phosphorylate Titin and Improve Diastolic Distensibility In Vivo
Authors: Kalkidan Bishu, Nazha Hamdani, Selma F. Mohammed, Martina Kruger, Tomohito Ohtani, Ozgur Ogut, Frank V. Brozovich, John C. Burnett, Wolfgang A. Linke, Margaret M. Redfield
Journal: Circulation (2011)

Background— In vitro studies suggest that phosphorylation of titin reduces myocyte/myofiber stiffness. Titin can be phosphorylated by cGMP-activated protein kinase. Intracellular cGMP production is stimulated by B-type natriuretic peptide (BNP) and degraded by phosphodiesterases, including phosphodiesterase-5A. We hypothesized that a phosphodiesterase-5A inhibitor (sildenafil) alone or in combination with BNP would increase left ventricular diastolic distensibility by phosphorylating titin. Methods and Results— Eight elderly dogs with experimental hypertension and 4 young normal dogs underwent measurement of the end-diastolic pressure-volume relationship during caval occlusion at baseline, after sildenafil, and BNP infusion. To assess diastolic distensibility independently of load/extrinsic forces, the end-diastolic volume at a common end-diastolic pressure on the sequential end-diastolic pressure-volume relationships was measured (left ventricular capacitance). In a separate group of dogs (n=7 old hypertensive and 7 young normal), serial full-thickness left ventricular biopsies were harvested from the beating heart during identical infusions to measure myofilament protein phosphorylation. Plasma cGMP increased with sildenafil and further with BNP (7.31±2.37 to 26.9±10.3 to 70.3±8.1 pmol/mL; P &lt;0.001). Left ventricular diastolic capacitance increased with sildenafil and further with BNP (51.4±16.9 to 53.7±16.8 to 60.0±19.4 mL; P &lt;0.001). Changes were similar in old hypertensive and young normal dogs. There were no effects on phosphorylation of troponin I, troponin T, phospholamban, or myosin light chain-1 or -2. Titin phosphorylation increased with sildenafil and BNP, whereas titin-based cardiomyocyte stiffness decreased. Conclusion— Short-term cGMP-enhancing treatment with sildenafil and BNP improves left ventricular diastolic distensibility in vivo, in part by phosphorylating titin.
SCGPred: A Score-Based Method for Gene Structure Prediction by Combining Multiple Sources of Evidence
Authors: Xiao Li, Qingan Ren, Yang Weng, Haoyang Cai, Yunmin Zhu, Yizheng Zhang
Journal: Genomics Proteomics & Bioinformatics (2008)

Abstract Predicting protein-coding genes still remains a significant challenge. Although a variety of computational programs that use commonly machine learning methods have emerged, the accuracy of predictions remains a low level when implementing in large genomic sequences. Moreover, computational gene finding in newly sequenced genomes is especially a difficult task due to the absence of a training set of abundant validated genes. Here we present a new gene-finding program, SCGPred, to improve the accuracy of prediction by combining multiple sources of evidence. SCGPred can perform both supervised method in previously well-studied genomes and unsupervised one in novel genomes. By testing with datasets composed of large DNA sequences from human and a novel genome of Ustilago maydi, SCGPred gains a significant improvement in comparison to the popular ab initio gene predictors. We also demonstrate that SCGPred can significantly improve prediction in novel genomes by combining several foreign gene finders with similarity alignments, which is superior to other unsupervised methods. Therefore, SCGPred can serve as an alternative gene-finding tool for newly sequenced eukaryotic genomes. The program is freely available at http://bio.scu.edu.cn/SCGPred/.
Early Mortality After Diagnosis of Multiple Myeloma: Analysis of Patients Entered Onto the United Kingdom Medical Research Council Trials Between 1980 and 2002—Medical Research Council Adult Leukaemia Working Party
Authors: Bradley M. Augustson, Gulnaz Begum, Janet A. Dunn, Nicola J. Barth, Faith Davies, Gareth Morgan, Judith Behrens, Alastair Smith, J. Anthony Child, Mark T. Drayson
Journal: Journal of Clinical Oncology (2005)

Early mortality in multiple myeloma (MM) is usually attributed to combined effects of active disease and comorbid factors. We have studied early deaths in a series of large multicenter trials to assess direct causes of death, their predictability, and whether current management strategies have reduced their frequency.A total of 3,107 newly diagnosed patients entered onto United Kingdom Medical Research Council MM trials from 1980 to 2002 were studied. Trial files, final clinical summaries, and postmortem reports were analyzed.Death within 60 days of trial entry occurred in 299 patients (10%). Logistic regression modeling identified beta 2-microglobulin, performance status, and age as the most important predictors of early death, but only with 61% sensitivity and 73% specificity. Forty-five percent of deaths were attributable to infection, which was often associated with bone pain (particularly thoracic pain) and delay in presenting to medical care. Neutropenia was present at diagnosis in only 11 of the 135 deaths from infection. Renal failure was present in 28% of early deaths and was linked to light-chain MM, hypercalcemia, dehydration, and nonsteroidal anti-inflammatory drugs. There was no time related reduction in the percentage or nature of early deaths in 1,550 patients older than 65 years receiving similar therapy between 1982 and 2002.A tenth of patients die within 60 days of diagnosis of MM. Infection and renal failure are the main direct causes of early mortality, which cannot be accurately predicted by presenting prognostic features. All patients should be considered at high risk of death during induction therapy.
Discrepancy Between Ultrasound and Oral Cholecystography in the Assessment of Gallstone Dissolution
Authors: Theodore F. Shapero, Irving E. Rosen, Stephanie R. Wilson, Murray M. Fisher
Journal: Hepatology (1982)

The Sunnybrook Medical Centre Gallstone Study is a randomized, controlled, double-blind study of chenodeoxycholic acid for dissolution of radiolucent gallstones. Of the first 22 patients whose stones were apparently totally dissolved on oral cholecystography, seven were found to have residual small stone fragments on ultrasound examination of the gallbladder. Continuing chenotherapy was unsuccessful in dissolving these fragments. The possibility that the residual stones represent insoluble nuclei of the original calculi must be considered. Responses to choleitholytic therapy and subsequent stone recurrences need to be reevaluated using ultrasound.
Defined αβ T Cell Receptors with Distinct Ligand Specificities Do Not Require Those Ligands to Signal Double Negative Thymocyte Differentiation
Authors: Batu Erman, Terry I. Guinter, Alfred Singer
Journal: The Journal of Experimental Medicine (2004)

During T cell development in the thymus, pre-T cell receptor (TCR) complexes signal CD4(-) CD8(-) (double negative [DN]) thymocytes to differentiate into CD4(+) CD8(+) (double positive [DP]) thymocytes, and they generate such signals without apparent ligand engagements. Although ligand-independent signaling is unusual and might be unique to the pre-TCR, it is possible that other TCR complexes such as alphabeta TCR or alphagamma TCR might also be able to signal the DN to DP transition in the absence of ligand engagement if they were expressed on DN thymocytes. Although alphagamma TCR complexes efficiently signal DN thymocyte differentiation, it is not yet certain if alphabeta TCR complexes are also capable of signaling DN thymocyte differentiation, nor is it certain if such signaling is dependent upon ligand engagement. This study has addressed these questions by expressing defined alphabeta TCR transgenes in recombination activating gene 2(-/-) pre-Talpha(-/-) double deficient mice. In such double deficient mice, the only antigen receptors that can be expressed are those encoded by the alphabeta TCR transgenes. In this way, this study definitively demonstrates that alphabeta TCR can in fact signal the DN to DP transition. In addition, this study demonstrates that transgenic alphabeta TCRs signal the DN to DP transition even in the absence of their specific MHC-peptide ligands.
Duration of immunosuppressive treatment for chronic graft-versus-host disease
Authors: Betty L. Stewart, Barry Storer, Jan Storek, H. Joachim Deeg, Rainer Storb, John A. Hansen, Frederick R. Appelbaum, Paul A. Carpenter, Jean E. Sanders, Hans-Peter Kiem, Richard A. Nash, Effie W. Petersdorf, Carina Moravec, A. James Morton, Claudio Anasetti, Mary E. D. Flowers, Paul J. Martin
Journal: Blood (2004)
Circulating Tumor Cell Biomarker Panel As an Individual-Level Surrogate for Survival in Metastatic Castration-Resistant Prostate Cancer
Authors: Howard I. Scher, Glenn Heller, Arturo Molina, Gerhardt Attard, Daniel C. Danila, Xiaoyu Jia, Weimin Peng, Shahneen K. Sandhu, David Olmos, Ruth Riisnaes, Robert McCormack, Tomasz Burzykowski, Thian Kheoh, Martin Fleisher, Marc Buyse, Johann S. de Bono
Journal: Journal of Clinical Oncology (2015)

Trials in castration-resistant prostate cancer (CRPC) need new clinical end points that are valid surrogates for survival. We evaluated circulating tumor cell (CTC) enumeration as a surrogate outcome measure.Examining CTCs alone and in combination with other biomarkers as a surrogate for overall survival was a secondary objective of COU-AA-301, a multinational, randomized, double-blind phase III trial of abiraterone acetate plus prednisone versus prednisone alone in patients with metastatic CRPC previously treated with docetaxel. The biomarkers were measured at baseline and 4, 8, and 12 weeks, with 12 weeks being the primary measure of interest. The Prentice criteria were applied to test candidate biomarkers as surrogates for overall survival at the individual-patient level.A biomarker panel using CTC count and lactate dehydrogenase (LDH) level was shown to satisfy the four Prentice criteria for individual-level surrogacy. Twelve-week surrogate biomarker data were available for 711 patients. The abiraterone acetate plus prednisone and prednisone-alone groups demonstrated a significant survival difference (P = .034); surrogate distribution at 12 weeks differed by treatment (P < .001); the discriminatory power of the surrogate to predict mortality was high (weighted c-index, 0.81); and adding the surrogate to the model eliminated the treatment effect on survival. Overall, 2-year survival of patients with CTCs < 5 (low risk) versus patients with CTCs ≥ 5 cells/7.5 mL of blood and LDH > 250 U/L (high risk) at 12 weeks was 46% and 2%, respectively.A biomarker panel containing CTC number and LDH level was shown to be a surrogate for survival at the individual-patient level in this trial of abiraterone acetate plus prednisone versus prednisone alone for patients with metastatic CRPC. Additional trials are ongoing to validate the findings.