tbuckley/cabot-search huggingface dataset:
Metabolic compartmentation of vertebrate glutamine synthetase: putative mitochondrial targeting signal in avian liver glutamine synthetase.
Authors: J W Campbell, D D Smith
Journal: Molecular Biology and Evolution (1992)

The evolution of uricoteley as a mechanism for hepatic ammonia detoxication in vertebrates required targeting of glutamine synthetase (GS) to liver mitochondria in the sauropsid line of descent leading to the squamate reptiles and archosaurs. Previous studies have shown that in birds and crocodilians, sole survivors of the archosaurian line, hepatic GS is translated without a transient, N-terminal targeting signal common to other mitochondrial matrix proteins. To identify a putative internal targeting sequence in the avian enzyme, the amino acid sequence of chicken liver GS was derived by a combination of sequencing of cloned cDNA, direct sequencing of mRNA, and sequencing of polymerase chain reaction (PCR) products amplified from reverse-transcribed mRNA. Analysis of the first 20 or so N-terminal amino acids of the derived sequence for the chicken enzyme shows that they are devoid of acidic amino acids, contain several hydroxy amino acids, and can be predicted to form a positively charged, amphipathic helix, all of which are characteristic properties of mitochondrial targeting signals. A comparison of the N-terminus of chicken GS with the N-termini of cytosolic mammalian GSs indicates that at least three amino acid replacements may have been responsible for converting the N-terminus of the cytosolic mammalian enzyme into a mitochondrial targeting signal. Two of these, His15 and Lys19, result in additional positive charges, as well as in changes in hydrophilicity. Both could have resulted from third-base-codon substitutions. A third replacement, Ala12, may contribute to the helicity of the N-terminus of the chicken enzyme. The N-terminus of the cytosolic chicken brain GS (positions 1-36) was found to be identical to that of the liver enzyme. The complete sequence of chicken retinal GS is also identical to that of the liver enzyme. GS is coded by a single gene in birds, so these sequence data suggest that, unlike the situation in other tissue-specific compartmental isozymes, differential targeting of avian GS to the mitochondrial or cytosolic compartments is not dependent on the sequence of the primary translation product of its mRNA but may involve some other tissue-specific factor(s).
Multipotentiality of Single Cells of Transplantable Teratocarcinomas Derived From Mouse Embryo Grafts
Authors: Jacques Jami, Evelyne Ritz
Journal: JNCI Journal of the National Cancer Institute (1974)

Sixteen clonal cultures from solid tumors of the embryo-derived teratocarcinoma line OTT 6050 were investigated histologically to determine whether the original tumors contained single pluripotent cells. Seven clones were derived from single cells picked up with micropipettes under a microscope. All tumors resulting from inoculation of cell clones into mice contained several tissue types derived from all 3 primary germ layers; this demonstrated that single cells from which clones were generated were pluripotent. In no clones were the potentialities restricted to one tissue type or to a group of related tissues.
RETRACTED: Prediction of Cardiovascular Events in Statin-Treated Stable Coronary Patients by Lipid and Nonlipid Biomarkers
Authors: Benoit J. Arsenault, Philip Barter, David A. DeMicco, Weihang Bao, Gregory M. Preston, John C. LaRosa, Scott M. Grundy, Prakash Deedwania, Heiner Greten, Nanette K. Wenger, James Shepherd, David D. Waters, John J.P. Kastelein
Journal: Journal of the American College of Cardiology (2010)
Further Evidence of Association Between Behavioral Inhibition and Social Anxiety in Children
Authors: J Biederman, D R Hirshfeld-Becker, J F Rosenbaum, C Hérot, D Friedman, N Snidman, J Kagan, S V Faraone
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The authors sought to examine psychopathological correlates of behavioral inhibition in young offspring of parents with panic disorder and/or major depression. METHOD: Behavioral inhibition, determined by using standard laboratory observations, was assessed in four groups of children (age 2–6 years): 129 children of parents with both panic disorder and major depression, 22 children of parents with panic disorder alone, 49 children of parents with major depression alone, and 84 comparison children of parents with neither panic disorder nor major depression. Psychopathology in children ≥5 years was compared between children with behavioral inhibition (N=64) and without (N=152). RESULTS: Social anxiety disorder (social phobia or avoidant disorder) was significantly more likely to be found in the children with behavioral inhibition (17%) than in those without (5%). Noninhibited children were significantly more likely than inhibited children to have disruptive behavior disorders (20% versus 6%, respectively) and had higher scores on the attention problems scale of the Child Behavior Checklist (mean=52.1 versus 50.8). CONCLUSIONS: This study adds to the growing literature suggesting an association between behavioral inhibition and social anxiety disorder and an inverse relationship between inhibition and disruptive behavior disorders.
Clinical Applications of His' Bundle Electrocardiography
Authors: H. Leon Greene
Journal: JAMA (1978)

Intracardiac ECG recording and stimulation are useful to evaluate conduction block, bradyarrhythmias, and tachyarrhythmias whose importance or mechanisms are uncertain from a surface ECG in the symptomatic patient. The technique is safe, with only rare complications. The response to medication can be tested during the procedure, helping to maximize the response to medical therapy. (<i>JAMA</i>240:258-260, 1978)
Cryotherapy for acute ankle sprains: a randomised controlled study of two different icing protocols
Authors: C M Bleakley, S M McDonough, D C MacAuley
Journal: British Journal of Sports Medicine (2006)

Background: The use of cryotherapy in the management of acute soft tissue injury is largely based on anecdotal evidence. Preliminary evidence suggests that intermittent cryotherapy applications are most effective at reducing tissue temperature to optimal therapeutic levels. However, its efficacy in treating injured human subjects is not yet known. Objective: : To compare the efficacy of an intermittent cryotherapy treatment protocol with a standard cryotherapy treatment protocol in the management of acute ankle sprains. Subjects: Sportsmen (n = 44) and members of the general public (n = 45) with mild/moderate acute ankle sprains. Methods: Subjects were randomly allocated, under strictly controlled double blind conditions, to one of two treatment groups: standard ice application (n = 46) or intermittent ice application (n = 43). The mode of cryotherapy was standardised across groups and consisted of melting iced water (0°C) in a standardised pack. Function, pain, and swelling were recorded at baseline and one, two, three, four, and six weeks after injury. Results: Subjects treated with the intermittent protocol had significantly (p&lt;0.05) less ankle pain on activity than those using a standard 20 minute protocol; however, one week after ankle injury, there were no significant differences between groups in terms of function, swelling, or pain at rest. Conclusion: Intermittent applications may enhance the therapeutic effect of ice in pain relief after acute soft tissue injury.
Androgen Metabolism and Prostate Cancer: Establishing a Model of Genetic Susceptibility
Authors: R.K. Ross, G.A. Coetzee, C.L. Pearce, J.K.V. Reichardt, P. Bretsky, L.N. Kolonel, B.E. Henderson, E. Lander, D. Altshuler, G. Daley
Journal: European Urology (1999)
Urinary incontinence in women
Authors: L. N. Wood, J. T. Anger
Journal: BMJ (2014)

Urinary incontinence affects women of all ages. History, physical examination, and certain tests can guide specialists in diagnosing stress urinary incontinence, urgency urinary incontinence, and mixed urinary incontinence. First line management includes lifestyle and behavior modification, as well as pelvic floor strength and bladder training. Drug therapy is helpful in the treatment of urgency incontinence that does not respond to conservative measures. In addition, sacral neuromodulation, intravesical onabotulinumtoxinA injections, and posterior tibial nerve stimulation can be used in select patient populations with drug refractory urgency incontinence. Midurethral synthetic slings, including retropubic and transobturator approaches, are safe and efficacious surgical options for stress urinary incontinence and have replaced more invasive bladder neck slings that use autologous or cadaveric fascia. Despite controversy surrounding vaginal mesh for prolapse, synthetic slings for the treatment of stress urinary incontinence are considered safe and minimally invasive.
NOS inhibition potentiates norepinephrine but not sympathetic nerve-mediated co-transmission in resistance arteries
Authors: K Smith
Journal: Cardiovascular Research (1999)

Objective: The in vitro interaction between sympathetic nerves and basal nitric oxide release was studied in a resistance artery, since these interact powerfully in large vessels. Methods: The pharmacological interaction between L-NAME and vasoconstriction to field stimulation of sympathetic nerves or exogenous norepinephrine was studied in rabbit cutaneous resistance arteries in wire myographs. Results: Relaxation of norepinephrine-induced tone by acetylcholine, but not sodium nitroprusside, was blocked by Nω-nitro-L-arginine methyl ester (L-NAME: 100 μM), indicating that the agonist-induced release of nitric oxide could oppose the vasoconstrictor effect of norepinephrine and confirming that L-NAME had no effect on endothelium-independent vasodilatation. L-NAME increased norepinephrine potency indicating basal NO release. With short bursts of electrical field stimulation purinergic transmission was dominant at low frequencies and adrenergic at high frequencies. L-NAME had no effect on nerve-mediated responses, even after blocking the purinergic component with α,β-methylene ATP (3 μM), suggesting that the influence of spontaneously released nitric oxide does not extend to the vascular smooth muscle cells under adrenergic nervous control. Conclusion(s): This resistance artery exhibits a highly effective nitric oxide-mediated vasodilatation to acetylcholine. It has basal release of nitric oxide which antagonises exogenous norepinephrine. However, basal nitric oxide did not influence adrenergic nerve transmission, which contrasts with previous studies of larger arteries and veins. We speculate that in small resistance arteries there may be a spatial limitation to the zones of vascular smooth muscle influenced by the adrenergic nerves and by basal nitric oxide from the endothelium, respectively. The role of endogenous nitric oxide in modulating vascular tone may thus be less in resistance arteries than in conducting arteries or capacitance vessels and purinergic transmission appears to be particularly resistant.
Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF
Authors: W E Lawson
Journal: Thorax (2004)

While idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease, the aetiology of IPF is poorly understood. Familial cases of pulmonary fibrosis suggest a genetic basis for some forms of the disease. Recent reports have linked genetic mutations in surfactant protein C (SFTPC) with familial forms of pulmonary fibrosis, including one large family in which a number of family members were diagnosed with usual interstitial pneumonitis (UIP), the pathological correlate to IPF. Because of this finding in familial cases of pulmonary fibrosis, we searched for SFTPC mutations in a cohort of sporadic cases of UIP and non-specific interstitial pneumonitis (NSIP).The gene for SFTPC was sequenced in 89 patients diagnosed with UIP, 46 patients with NSIP, and 104 normal controls.Ten single nucleotide polymorphisms in the SFTPC sequence were found in IPF patients and not in controls. Only one of these created an exonic change resulting in a change in amino acid sequence. In this case, a T to C substitution resulted in a change in amino acid 73 of the precursor protein from isoleucine to threonine. Of the remaining polymorphisms, one was in the 5' UTR, two were exonic without predicted amino acid sequence changes, and six were intronic. One intronic mutation suggested a potential enhancement of a splicing site.Mutations in SFTPC are identified infrequently in this patient population. These findings indicate that SFTPC mutations do not contribute to the pathogenesis of IPF in the majority of sporadic cases.
Health Information on the Internet
Authors: G K Berland, M N Elliott, L S Morales, J I Algazy, R L Kravitz, M S Broder, D E Kanouse, J A Muñoz, J A Puyol, M Lara, K E Watkins, H Yang, E A McGlynn
Journal: JAMA (2001)

Despite the substantial amount of health-related information available on the Internet, little is known about the accessibility, quality, and reading grade level of that health information.
Evolution and Cytological Diversification of the Green Seaweeds (Ulvophyceae)
Authors: E. Cocquyt, H. Verbruggen, F. Leliaert, O. De Clerck
Journal: Molecular Biology and Evolution (2010)

The Ulvophyceae, one of the four classes of the Chlorophyta, is of particular evolutionary interest because it features an unrivaled morphological and cytological diversity. Morphological types range from unicells and simple multicellular filaments to sheet-like and complex corticated thalli. Cytological layouts range from typical small cells containing a single nucleus and chloroplast to giant cells containing millions of nuclei and chloroplasts. In order to understand the evolution of these morphological and cytological types, the present paper aims to assess whether the Ulvophyceae are monophyletic and elucidate the ancient relationships among its orders. Our approach consists of phylogenetic analyses (maximum likelihood and Bayesian inference) of seven nuclear genes, small subunit nuclear ribosomal DNA and two plastid markers with carefully chosen partitioning strategies, and models of sequence evolution. We introduce a procedure for fast site removal (site stripping) targeted at improving phylogenetic signal in a particular epoch of interest and evaluate the specificity of fast site removal to retain signal about ancient relationships. From our phylogenetic analyses, we conclude that the ancestral ulvophyte likely was a unicellular uninucleate organism and that macroscopic growth was achieved independently in various lineages involving radically different mechanisms: either by evolving multicellularity with coupled mitosis and cytokinesis (Ulvales—Ulotrichales and Trentepohliales), by obtaining a multinucleate siphonocladous organization where every nucleus provides for its own cytoplasmic domain (Cladophorales and Blastophysa), or by developing a siphonous organization characterized by either one macronucleus or millions of small nuclei and cytoplasmic streaming (Bryopsidales and Dasycladales). We compare different evolutionary scenarios giving rise to siphonous and siphonocladous cytologies and argue that these did not necessarily evolve from a multicellular or even multinucleate state but instead could have evolved independently from a unicellular ancestor.
Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans
Authors: Marina Caskey, François Lefebvre, Abdelali Filali-Mouhim, Mark J. Cameron, Jean-Philippe Goulet, Elias K. Haddad, Gaëlle Breton, Christine Trumpfheller, Sarah Pollak, Irina Shimeliovich, Angela Duque-Alarcon, Li Pan, Annette Nelkenbaum, Andres M. Salazar, Sarah J. Schlesinger, Ralph M. Steinman, Rafick P. Sékaly
Journal: The Journal of Experimental Medicine (2011)

Adjuvants are critical for the success of vaccines. Agonists of microbial pattern recognition receptors (PRRs) are promising new adjuvant candidates. A mechanism through which adjuvants enhance immune responses is to stimulate innate immunity. We studied the innate immune response in humans to synthetic double-stranded RNA (polyinosinic:polycytidylic acid [poly IC] stabilized with poly-l-lysine [poly ICLC]), an agonist for toll-like receptor (TLR) 3, and the cytosolic RNA helicase MDA-5. Transcriptional analysis of blood samples from eight volunteers, after subcutaneous administration of poly ICLC, showed up-regulation of genes involved in multiple innate immune pathways in all subjects, including interferon (IFN) and inflammasome signaling. Blocking type I IFN receptor ex vivo significantly dampened the response to poly IC. Comparative transcriptional analysis showed that several innate immune pathways were similarly induced in volunteers immunized with the highly efficacious yellow fever vaccine. Therefore, a chemically defined PRR agonist like poly ICLC can be a reliable and authentic microbial mimic for inducing innate immune responses in humans.
Key findings towards optimising adalimumab treatment: the concentration–effect curve
Authors: Mieke F Pouw, Charlotte L Krieckaert, Michael T Nurmohamed, Desiree van der Kleij, Lucien Aarden, Theo Rispens, Gertjan Wolbink
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To determine a concentration–effect curve of adalimumab in rheumatoid arthritis (RA) patients taking into account the effect of methotrexate (MTX) on concentration and effect and to identify a therapeutic range for adalimumab concentrations. <h3>Methods</h3> In a prospective observational cohort study, 221 consecutive patients with RA were treated with 40 mg adalimumab subcutaneously every other week. The relationship between adalimumab trough level and clinical efficacy after 28 weeks of follow-up was determined in a concentration–effect curve. A receiver–operator characteristics (ROC) curve established a therapeutic cut-off concentration. The effect of MTX on adalimumab trough levels was shown by dividing patients that are and are not concomitantly using MTX in the concentration–effect curve and a concentration table. <h3>Results</h3> Clinical efficacy improved with increasing adalimumab concentration and reached a maximum (mean disease activity score in 28 joints improvement of 2) with levels between 5–8 μg/mL. Levels exceeding 8 μg/mL were illustrated to have no additional beneficial effect on disease activity. The ROC curve showed an area under the curve of 0.695 (95% CI 0.626 to 0.764) for European League Against Rheumatism response and adalimumab levels: good responders versus non-responders and moderate responders. A cut-off of 5 μg/mL had a sensitivity of 91% and a specificity of 43%. Adalimumab levels are influenced by concomitant MTX use: patients on adalimumab monotherapy had a median adalimumab level of 4.1 μg/mL (IQR 1.3–7.7), whereas patients concomitantly taking MTX had a median level of 7.4 μg/mL (IQR 5.3–10.6, p&lt;0.001). <h3>Conclusions</h3> Adalimumab trough levels in a range of 5–8 μg/mL are sufficient to reach adequate clinical response. These levels are influenced substantially by concomitant MTX use.
Restricted secretion of a T-lymphocyte chemotactic cytokine by serotonin-stimulated cultured aortic endothelial cells.
Authors: H W Farber, D J Beer
Journal: Circulation Research (1991)

The diversity of biologically active molecules produced by vascular endothelium suggests that the endothelial cell is an active participant in numerous physiological responses, including those of the immune system. In fact, the accumulation of T lymphocytes at extralymphatic inflammatory foci represents a series of interactions between lymphocytes and vascular endothelial cells. These interactions, however, may be modulated by other factors, such as vasoactive amines. In the current study, we report that serotonin-stimulated cultured bovine aortic endothelial cells (BAECs) secrete a T-lymphocyte chemotactic cytokine (endothelial cell-derived lymphocyte chemotactic activity [ED-LCA]). Supernatants from BAECs incubated with 10(-7)-10(-4) M serotonin (5-hydroxytryptamine [5-HT]) enhanced T-cell migration, which peaked at 10(-5) M 5-HT (235 +/- 18% control migration). ED-LCA was not stored in an active form in BAECs; its secretion occurred within 60 minutes of exposure to 5-HT and was blocked by two different 5-HT2 receptor antagonists. ED-LCA was not secreted after exposure of BAECs to histamine or angiotensin II, nor was it secreted by either 5-HT-stimulated bovine pulmonary arterial or human umbilical vein endothelial cells. Physicochemical characterization of ED-LCA demonstrated that it was a trypsin-sensitive protein with an apparent molecular mass of 13-15 kDa. Preparative isoelectric focusing demonstrated pIs of 6.0 and 7.5. When applied to a molecular sieve column, the chemotactic activity corresponding to these pIs eluted in the region of 13-15 kDa. Further investigation demonstrated that partially purified ED-LCA was specific for CD4+ and CD8+ T-lymphocyte subsets and did not enhance the migration of neutrophils or monocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
New Therapeutic Approaches to Crohn's Disease
Authors: R. Balfour Sartor
Journal: New England Journal of Medicine (2000)

Crohn's disease is an idiopathic, immunologically mediated disorder in which medically or surgically induced remissions are followed by relapses. The goals of treatment are to induce and then maintain remission through the long-term use of nontoxic agents.1 Several medications that are effective in the short term do not result in sustained remission, and conversely, agents used for maintenance may have minimal effects on active disease. For example, prednisone usually suppresses active inflammation, but long-term use is associated with high rates of relapse and unacceptable toxicity. The most effective drugs for maintenance therapy — mercaptopurine and azathioprine — have limited immediate . . .
Mobile elements in the human genome: implications for disease
Authors: Szilvia Solyom, Haig H Kazazian
Journal: Genome Medicine (2012)

Perhaps as much as two-thirds of the mammalian genome is composed of mobile genetic elements ('jumping genes'), a fraction of which is still active or can be reactivated. By their sheer number and mobility, retrotransposons, DNA transposons and endogenous retroviruses have shaped our genotype and phenotype both on an evolutionary scale and on an individual level. Notably, at least the non-long terminal repeat retrotransposons are still able to cause disease by insertional mutagenesis, recombination, providing enzymatic activities for other mobile DNA, and perhaps by transcriptional overactivation and epigenetic effects. Currently, there are nearly 100 examples of known retroelement insertions that cause disease. In this review, we highlight those genome-scale technologies that have expanded our knowledge of the diseases that these mobile elements can elicit, and we discuss the potential impact of these findings for medicine. It is now likely that at least some types of cancer and neurological disorders arise as a result of retrotransposon mutagenesis.
Epidemiology of fibrolamellar hepatocellular carcinoma in the USA, 2000–10
Authors: Tobias Eggert, Katherine A McGlynn, Austin Duffy, Michael Peter Manns, Tim F Greten, Sean F Altekruse
Journal: Gut (2013)

We read with great interest the article by Tremosini et al 1 in Gut , which prospectively validated the use of a panel of three antibodies (glypican 3, heat shock protein 70 and glutamine synthetase) for the histopathological diagnosis of hepatocellularcarcinoma (HCC). According to the international classification of diseases for oncology,2 HCC are classified into HCC not otherwise specified (HCC-NOS), which accounts for the vast majority of HCC, fibrolamellar HCC (fHCC), scirrhous HCC, spindle cell variant HCC, clear cell HCC and pleomorphic HCC. While many studies including that by Tremosini and colleagues1 restrict their focus to HCC-NOS, we decided to study fHCC in more depth. fHCC is a rare tumour with limited clinical information available. Current data suggest that demographic attributes of fHCC cases are very different …