tbuckley/cabot-search huggingface dataset:
Effects of salmeterol on mucosal inflammation in asthma: a placebo-controlled study
Authors: P.K. Jeffery, P. Venge, M.J. Gizycki, I. Egerod, R. Dahl, P. Faurschou
Journal: European Respiratory Journal (2002)

Although the anti-inflammatory effects of inhaled corticosteroids in the treatment of asthma are established, the effects of long-acting β 2 -adrenergic receptor agonists on inflammation are the subject of debate. The aim of the present study was to determine the effect of salmeterol on the numbers of inflammatory cells in biopsy samples of distinct immunophenotype and those expressing the genes for interleukin-4 and -5, regulatory cytokines particularly relevant to asthma. Twenty patients (aged 18–55 yrs) with mild stable asthma were randomised in a three-way crossover study to 6 weeks of treatment with: 1) salmeterol (50 µg b.d. ; SM 50 ); 2) fluticasone propionate (250 µg b.d. ; FP 250 ), or 3) placebo. Compared with placebo, SM 50 significantly reduced the numbers of neutrophils in bronchial biopsy samples and the concentrations of myeloperoxidase and soluble E-selectin in serum, each of which reflect neutrophil involvement. Compared with FP 250 , SM 50 reduced neutrophil number and human neutrophil lipocalin level in bronchial lavage fluid and intercellular adhesion molecule-1 level in bronchoalveolar lavage fluid. Compared with placebo, FP 250 significantly reduced the numbers of (CD3+) T-lymphocytes, (CD4+) T-helper cells, (CD45RO+) activated T-helper cells and eosinophils in the biopsy samples; it also reduced the percentage of eosinophils and soluble intercellular adhesion molecule-1 in serum. The percentage of symptom-free days and nights and airways hyperresponsiveness improved significantly after SM 50 compared to both placebo and FP 250 . In conclusion, a novel antineutrophilic effect of the inhaled long-acting β 2 -adrenergic receptor agonist, salmeterol, in mild asthma is reported.
Intractable diarrhoea of infancy caused by neutrophil specific granule deficiency and cured by stem cell transplantation
Authors: R F Wynn
Journal: Gut (2006)

Intractable diarrhoea of infancy (IDI) can often become life threatening and still poses a major diagnostic challenge. It embraces a diverse group of disorders1 and in a significant number of infants the underlying cause cannot be identified. We describe a child who presented with IDI where routine investigations were unhelpful, but more detailed tests of neutrophil function revealed a congenital defect of neutrophil specific granule formation.

A three week old baby girl of Pakistani origin of non-consanguineous parents living in the UK was referred because of pyrexia of unknown origin, as well as vomiting and severe watery diarrhoea associated with failure to thrive. Rhodococcus equi isolated after repeated blood culture responded to treatment with teicoplanin and Co-trimoxazole. The umbilical cord finally separated at five weeks of age. No pathogens were isolated from repeated stool cultures. …
The evolution, impact and properties of exonic splice enhancers
Authors: Eva Fernández Cáceres, Laurence D Hurst
Journal: Genome biology (2013)

In humans, much of the information specifying splice sites is not at the splice site. Exonic splice enhancers are one of the principle non-splice site motifs. Four high-throughput studies have provided a compendium of motifs that function as exonic splice enhancers, but only one, RESCUE-ESE, has been generally employed to examine the properties of enhancers. Here we consider these four datasets to ask whether there is any consensus on the properties and impacts of exonic splice enhancers.While only about 1% of all the identified hexamer motifs are common to all analyses we can define reasonably sized sets that are found in most datasets. These consensus intersection datasets we presume reflect the true properties of exonic splice enhancers. Given prior evidence for the properties of enhancers and splice-associated mutations, we ask for all datasets whether the exonic splice enhancers considered are purine enriched; enriched near exon boundaries; able to predict trends in relative codon usage; slow evolving at synonymous sites; rare in SNPs; associated with weak splice sites; and enriched near longer introns. While the intersect datasets match expectations, only one original dataset, RESCUE-ESE, does. Unexpectedly, a fully experimental dataset identifies motifs that commonly behave opposite to the consensus, for example, being enriched in exon cores where splice-associated mutations are rare.Prior analyses that used the RESCUE-ESE set of hexamers captured the properties of consensus exonic splice enhancers. We estimate that at least 4% of synonymous mutations are deleterious owing to an effect on enhancer functioning.
Peripheral nervous system plasmalogens regulate Schwann cell differentiation and myelination
Authors: Tiago Ferreira da Silva, Jessica Eira, André T. Lopes, Ana R. Malheiro, Vera Sousa, Adrienne Luoma, Robin L. Avila, Ronald J.A. Wanders, Wilhelm W. Just, Daniel A. Kirschner, Mónica M. Sousa, Pedro Brites
Journal: Journal of Clinical Investigation (2014)

Rhizomelic chondrodysplasia punctata (RCDP) is a developmental disorder characterized by hypotonia, cataracts, abnormal ossification, impaired motor development, and intellectual disability. The underlying etiology of RCDP is a deficiency in the biosynthesis of ether phospholipids, of which plasmalogens are the most abundant form in nervous tissue and myelin; however, the role of plasmalogens in the peripheral nervous system is poorly defined. Here, we used mouse models of RCDP and analyzed the consequence of plasmalogen deficiency in peripheral nerves. We determined that plasmalogens are crucial for Schwann cell development and differentiation and that plasmalogen defects impaired radial sorting, myelination, and myelin structure. Plasmalogen insufficiency resulted in defective protein kinase B (AKT) phosphorylation and subsequent signaling, causing overt activation of glycogen synthase kinase 3β (GSK3β) in nerves of mutant mice. Treatment with GSK3β inhibitors, lithium, or 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) restored Schwann cell defects, effectively bypassing plasmalogen deficiency. Our results demonstrate the requirement of plasmalogens for the correct and timely differentiation of Schwann cells and for the process of myelination. In addition, these studies identify a mechanism by which the lack of a membrane phospholipid causes neuropathology, implicating plasmalogens as regulators of membrane and cell signaling.
A 52-year-old man with heartburn and weight loss
Authors: Giuseppe Gizzi, Maria Pia Foschini, Carlo Fabbri, Lorenzo Fuccio
Journal: Gut (2015)

A previously fit and well 52-year-old man presented to the hospital with a 3-month history of refractory heartburn and progressive weight loss (5 kg). After an initial response to empiric treatment with 20 mg omeprazole daily, heartburn relapsed and became refractory to proton pump inhibitor. His past medical history and physical examination were unremarkable. Upper endoscopy showed a thick white membrane in the distal part of the oesophagus, crossing the gastro-oesophageal junction (figure 1A); the mucosa surrounding the distal margin was slightly depressed but not reddened. An initial diagnosis of candidosis was suggested and …
Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma: A novel role for S-adenosylmethionine
Authors: M.A. Avila, C. Berasain, E.R. García-Trevijano, J. Caballería, M.U. Latasa, M.V. Carretero, H. Yang, L. Torres, J. Prieto, S.C. Lu, J. Rodés, J.M. Mato
Journal: Journal of Hepatology (2000)
Cancer and lesbian, gay, bisexual, transgender/transsexual, and queer/questioning (LGBTQ) populations
Authors: Gwendolyn P. Quinn, Julian A. Sanchez, Steven K. Sutton, Susan T. Vadaparampil, Giang T. Nguyen, B. Lee Green, Peter A. Kanetsky, Matthew B. Schabath
Journal: CA A Cancer Journal for Clinicians (2015)

This article provides an overview of the current literature on seven cancer sites that may disproportionately affect lesbian, gay, bisexual, transgender/transsexual, and queer/questioning (LGBTQ) populations. For each cancer site, the authors present and discuss the descriptive statistics, primary prevention, secondary prevention and preclinical disease, tertiary prevention and late‐stage disease, and clinical implications. Finally, an overview of psychosocial factors related to cancer survivorship is offered as well as strategies for improving access to care. CA Cancer J Clin 2015;65:384–400. © 2015 American Cancer Society .
Type I Collagen Limits VEGFR-2 Signaling by a SHP2 Protein-Tyrosine Phosphatase–Dependent Mechanism 1
Authors: Stefania Mitola, Barbara Brenchio, Marco Piccinini, Leon Tertoolen, Luca Zammataro, Georg Breier, Maria Teresa Rinaudo, Jeroen den Hertog, Marco Arese, Federico Bussolino
Journal: Circulation Research (2005)

During angiogenesis, a combined action between newly secreted extracellular matrix proteins and the repertoire of integrins expressed by endothelial cells contributes in the regulation of their biological functions. Extracellular matrix-engaged integrins influence tyrosine kinase receptors, thus promoting a regulatory cross-talk between adhesive and soluble stimuli. For instance, vitronectin has been reported to positively regulate VEGFR-2. Here, we show that collagen I downregulates VEGF-A-mediated VEGFR-2 activation. This activity requires the tyrosine phosphatase SHP2, which is recruited to the activated VEGFR-2 when cells are plated on collagen I, but not on vitronectin. Constitutive expression of SHP2(C459S) mutant inhibits the negative role of collagen I on VEGFR-2 phosphorylation. VEGFR-2 undergoes internalisation, which is associated with dynamin II phosphorylation. Expression of SHP2(C459S) impairs receptor internalisation suggesting that SHP2-dependent dephosphorylation regulates this process. These findings demonstrate that collagen I in provisional extracellular matrix surrounding nascent capillaries triggers a signaling pathway that negatively regulates angiogenesis.
Spontaneous Mutations in Digestive Tract of Old Mice Show Tissue-Specific Patterns of Genomic Instability
Authors: Tetsuya Ono, Hironobu Ikehata, Vishnu Priya Pithani, Yoshihiko Uehara, Yali Chen, Yoshitaka Kinouchi, Toru Shimosegawa, Yoshio Hosoi
Journal: Cancer Research (2004)

In an attempt to evaluate the possible role of mutations in the age-dependent increase of tumor incidence, we studied the mutational burden that accumulates in the aging process in different parts of the digestive tract in mice. The mutations were monitored in lacZ genes integrated in the mouse genome. The digestive tract was divided into the esophagus, stomach, proximal, medial, and distal part of the small intestine, and the colon. Epithelial tissues were separated from these tissues with the exception of the esophagus, in which case the whole tissue was examined. At a young age, the mutant frequencies as well as the molecular nature of the mutations were similar among the tissues examined. In old age, on the other hand, mutant frequencies were elevated to different degrees among the tissues; they were high in the small intestine and colon, intermediate in the stomach, and low in the esophagus. The molecular characteristics of the mutations also revealed distinct tissue-specificity; there were elevated rates of a small deletion mutation in the esophagus, G:C to T:A transversion in the proximal small intestine, and multiple mutations in the distal small intestine and colon. The results indicate that different parts of the digestive tract suffer from different kinds of mutational stress in the aging process. The nature of the multiple mutations suggests the presence of a mutator phenotype based on an imbalance in deoxyribonucleotide pools.
Comparison of solution-based exome capture methods for next generation sequencing
Authors: Anna-Maija Sulonen, Pekka Ellonen, Henrikki Almusa, Maija Lepistö, Samuli Eldfors, Sari Hannula, Timo Miettinen, Henna Tyynismaa, Perttu Salo, Caroline Heckman, Heikki Joensuu, Taneli Raivio, Anu Suomalainen, Janna Saarela
Journal: Genome biology (2011)

Abstract Background Techniques enabling targeted re-sequencing of the protein coding sequences of the human genome on next generation sequencing instruments are of great interest. We conducted a systematic comparison of the solution-based exome capture kits provided by Agilent and Roche NimbleGen. A control DNA sample was captured with all four capture methods and prepared for Illumina GAII sequencing. Sequence data from additional samples prepared with the same protocols were also used in the comparison. Results We developed a bioinformatics pipeline for quality control, short read alignment, variant identification and annotation of the sequence data. In our analysis, a larger percentage of the high quality reads from the NimbleGen captures than from the Agilent captures aligned to the capture target regions. High GC content of the target sequence was associated with poor capture success in all exome enrichment methods. Comparison of mean allele balances for heterozygous variants indicated a tendency to have more reference bases than variant bases in the heterozygous variant positions within the target regions in all methods. There was virtually no difference in the genotype concordance compared to genotypes derived from SNP arrays. A minimum of 11× coverage was required to make a heterozygote genotype call with 99% accuracy when compared to common SNPs on genome-wide association arrays. Conclusions Libraries captured with NimbleGen kits aligned more accurately to the target regions. The updated NimbleGen kit most efficiently covered the exome with a minimum coverage of 20×, yet none of the kits captured all the Consensus Coding Sequence annotated exons.
Does "afternoon diabetes" predict diabetes?
Authors: R J Jarrett, G C Viberti, H A Sayegh
Journal: BMJ (1978)

Twenty-eight men were given morning and afternoon oral glucose tolerance tests in 1969 and again in 1975. According to British Diabetic Association criteria all 28 had normal morning values in 1969 but seven had "afternoon diabetes". Four men had diabetic values in the morning in 1975 but only two of these had had afternoon diabetes in 1969. Better prediction of subsequent diabetes was obtained by calculating the area under the morning glucose tolerance curve in 1969. All four men who progressed to diabetes had areas exceeding 1000 units, which distinguished them absolutely from the other 24. They also tended to be more obese, but this was less predictive of subsequent diabetes.
Is Previous Respiratory Disease a Risk Factor for Lung Cancer?
Authors: Rachel Denholm, Joachim Schüz, Kurt Straif, Isabelle Stücker, Karl-Heinz Jöckel, Darren R. Brenner, Sara De Matteis, Paolo Boffetta, Florence Guida, Irene Brüske, Heinz-Erich Wichmann, Maria Teresa Landi, Neil Caporaso, Jack Siemiatycki, Wolfgang Ahrens, Hermann Pohlabeln, David Zaridze, John K. Field, John McLaughlin, Paul Demers, Neonila Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Rodica Stanescu Dumitru, Vladimir Bencko, Lenka Foretova, Vladimir Janout, Benjamin Kendzia, Susan Peters, Thomas Behrens, Roel Vermeulen, Thomas Brüning, Hans Kromhout, Ann C. Olsson
Journal: American Journal of Respiratory and Critical Care Medicine (2014)

Previous respiratory diseases have been associated with increased risk of lung cancer. Respiratory conditions often co-occur and few studies have investigated multiple conditions simultaneously.
THE EFFECT OF ANTISERUM, ALONE AND WITH HYDROCORTISONE, ON FOETAL MOUSE BONES IN CULTURE
Authors: Honor B. Fell, L. Weiss
Journal: The Journal of Experimental Medicine (1965)

1. The effects of normal rabbit serum and of rabbit antiserum to whole foetal mouse tissues, on the isolated limb bones of late foetal mice were studied in organ culture, and the influence of hydrocortisone on these effects was investigated. 2. Unheated normal serum caused slight loss of metachromatic material from the cartilage matrix, and some resorption of both cartilage and bone. 3. In unheated antiserum to foetal mouse tissues, the terminal cartilage was smaller and less metachromatic than in paired controls in normal serum, while osteoclasis was so intense that in many explants the bone had almost disappeared. The amount of necrosis varied with different batches of antiserum. 4. The changes produced by normal serum and antiserum could be largely prevented by heating the sera to 57 degrees C for 45 minutes. 5. The effects could also be inhibited by the addition of hydrocortisone to the unheated sera; as little as 0.1 microg hydrocortisone per ml of medium had a well marked protective action. 6. It is suggested that (a) unheated antiserum causes a release of lysosomal enzymes with consequent breakdown of intercellular material, (b) this release is due to an indirect action on the lysosome via an increased permeability of the cell membrane, (c) hydrocortisone does not affect the antigen-antibody reaction, but inhibits the autolytic changes that normally follow this reaction, possibly by stabilising both the lysosomal and cell membranes.
Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function
Authors: V. A. Maltsev, E. G. Lakatta
Journal: Cardiovascular Research (2007)

For almost half a century it has been thought that the initiation of each heartbeat is driven by surface membrane voltage-gated ion channels (M clocks) within sinoatrial nodal cells. It has also been assumed that pacemaker cell automaticity is initiated at the maximum diastolic potential (MDP). Recent experimental evidence based on confocal cell imaging and supported by numerical modelling, however, shows that initiation of cardiac impulse is a more complex phenomenon and involves yet another clock that resides under the sarcolemma. This clock is the sarcoplasmic reticulum (SR): it generates spontaneous, but precisely timed, rhythmic, submembrane, local Ca(2+) releases (LCR) that appear not at the MDP but during the late, diastolic depolarization (DD). The Ca(2+) clock and M clock dynamically interact, defining a novel paradigm of robust cardiac pacemaker function and regulation. Rhythmic LCRs during the late DD activate inward Na(+)/Ca(2+) exchanger currents and ignite action potentials, which in turn induceCa(2+) transients and SR depletions, resetting the Ca(2+) clock. Both basal and reserve protein kinaseA-dependent phosphorylation of Ca(2+) cycling proteins control the speed and amplitude of SR Ca(2+) cycling to regulate the beating rate by strongly coupled Ca(2+) and M clocks.
Laboratory-Acquired North American Blastomycosis
Authors: J. Fred Denton
Journal: JAMA (1967)

LABORATORY-ACQUIRED infections with<i>Blastomyces dermatitidis</i>, including infections acquired by persons performing autopsies on patients who died of blastomycosis, have been reported rarely. Of the five cases described in the literature, three resulted from inoculation of fingers with the parasitic form of the fungus during autopsy. The three cases demonstrate the danger of this type of exposure.<sup>1-3</sup>The other two cases involved a pathologist who infected himself in the wrist from a culture of<i>B dermatitidis</i>of unspecified morphological form and a graduate student who inoculated his finger with a culture of the parasitic form of this organism.<sup>3,4</sup>This report describes the first infection presumed to have been acquired in the laboratory from inhalation of conidia from the saprophytic form of the fungus and establishes the danger from this source. <h3>Report of a Case</h3> On Sept 13, 1963, a 30-year-old Negro woman began working as a laboratory assistant in
PDT in early central lung cancer
Authors: L. Freitag
Journal: Thorax (2007)

Resources are needed to use the full potential of photodynamic therapy

In this issue of Thorax, Moghissi et al 1 report their experience of treating a selected group of patients with porphyrin-based photodynamic therapy (PDT) ( see p 391 ). These patients had localised early bronchogenic carcinomas without lymphadenopathy or distant metastases. They could not undergo surgery because of their overall clinical condition and half of them had been operated on before. Recognised as a world class thoracic surgeon, Mr Moghissi is certainly not questioning the value of surgery. Only after alternatives such as parenchymal-sparing bronchoplasty had been definitely excluded was PDT with curative intent offered. PDT was applied with a single laser light illumination using rigid bronchoscopy under general anaesthesia. Such a treatment usually takes less than 20 minutes, and at the Yorkshire Laser Centre it is performed as a day case procedure.

This is a solid and honest report from probably Europe’s most active PDT centre. At first sight the statement that “complete response was achieved in all of the 21 patients” builds a strong case for this type of treatment. …
Clinical Trials Design Lessons From the CATIE Study
Authors: Helena Chmura Kraemer, Ira D Glick, Donald F Klein
Journal: American Journal of Psychiatry (2009)

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study was funded by the National Institute of Mental Health to compare the effectiveness of drugs for schizophrenia. The focus here is not on its conclusions but on the knotty issues of design and methods, in order to support appropriate clinical interpretation of the conclusions, and on using the CATIE experience to indicate directions for improvement of future clinical trials. While many of the CATIE design and implementation decisions are excellent and serve as models for future research, other decisions resulted in a study with a large study group but inadequate power. Multiple treatment interventions, unbalanced randomization within and across clinical sites, and multiple secondary outcomes are among the issues that require even more serious consideration in future large multisite clinical trials. Moreover, it is crucial to clarify whether the intent of a study is to establish superiority of some treatments or to establish equivalence, for the appropriate designs and analyses differ in these situations. If the study is designed, as was CATIE, to demonstrate some treatments' superiority, statistically nonsignificant results should not be misinterpreted as evidence of "equivalence." For establishing either superiority or equivalence, future treatment comparisons might better be designed with fewer sites, more subjects per site, fewer treatments, and fewer outcomes, in order to have the power for definitively establishing superiority or equivalence at a lower cost.
Targeting Melanocortin Receptors as a Novel Strategy to Control Inflammation
Authors: Anna Catania, Stefano Gatti, Gualtiero Colombo, James M. Lipton
Journal: Pharmacological Reviews (2004)

Adrenocorticotropic hormone and alpha-, beta-, and gamma-melanocyte-stimulating hormones, collectively called melanocortin peptides, exert multiple effects upon the host. These effects range from modulation of fever and inflammation to control of food intake, autonomic functions, and exocrine secretions. Recognition and cloning of five melanocortin receptors (MCRs) has greatly improved understanding of peptide-target cell interactions. Preclinical investigations indicate that activation of certain MCR subtypes, primarily MC1R and MC3R, could be a novel strategy to control inflammatory disorders. As a consequence of reduced translocation of the nuclear factor kappaB to the nucleus, MCR activation causes a collective reduction of the major molecules involved in the inflammatory process. Therefore, anti-inflammatory influences are broad and are not restricted to a specific mediator. Short half-life and lack of selectivity could be an obstacle to the use of the natural melanocortins. However, design and synthesis of new MCR ligands with selective chemical properties are already in progress. This review examines how marshaling MCR could control inflammation.