tbuckley/cabot-search huggingface dataset:
Mixed genotype hepatitis C infections and implications for treatment
Authors: Anna L. McNaughton, Emma C. Thomson, Kate Templeton, Rory N. Gunson, Carol E. McWilliam Leitch
Journal: Hepatology (2013)

The recently licensed direct-acting antivirals (DAAs) boceprevir and telaprevir used to treat hepatitis C virus (HCV) infection act in a genotype-specific manner. The potential outcome of DAA treatment regimes on mixed HCV infections, consisting of concurrent infection with more than one HCV genotype, has not been considered. Standard genotyping methods are only capable of identifying the dominant genotype present within a mixed infection sample, leaving minor genotypes undetected. We propose that DAA treatment of mixed infections may be associated with the occurrence of genotype switching, whereby a previously undetected minority variant drug-resistant genotype expands to replace the successfully treated majority variant genotype. Such genotype switching could in some cases result in nonresponse to DAA treatment and could also be incorrectly interpreted as reinfection if genotyping is not repeated following treatment failure. As a matter of urgency, there is a need to assess the prevalence and clinical impact of mixed HCV infections. To determine the prevalence of mixed HCV infections in a cohort of patients infected with genotype (gt) 3a (n = 47) or 1a (n = 48), we designed gt1a- and gt3a-specific primers providing partial coverage of the envelope genes E1 and E2 of HCV. Nested reverse transcription (RT) polymerase chain reaction (PCR) reactions were performed using gt1a primers with gt3a-infected samples and vice versa. Amplicons were sequenced and used to construct maximum likelihood phylogenetic trees using the MEGA 5.0 software package to confirm genotype. The sensitivity of the RT-PCR reactions, as determined by 90% detection limits calculated from serial endpoint dilution RT-PCR and probit analysis, was nine copies/reaction. Of the gt3a-infected patient samples, 10.6% (5/47) harbored minority variant gt1a strains, whereas none of the gt1a-infected patient samples contained gt3a as a minority strain. These findings are in keeping with other studies that found mixed HCV infections at rates of 5%-25.3%.1-3 Further work is required to assess the impact of minority variant strains on patients treated with DAA therapy. If relapse following dual therapy for gt3 infection is associated with emerging dominance of preexisting gt1 strains, screening of baseline patient samples using genotype-specific methods could result in improved treatment strategies; for example, the prescription of triple rather than dual antiviral therapy. More work is required to assess the impact of multiple genotype infection on clinical outcome, and this work is more pressing in the DAA era. Anna L. McNaughton, M.Sc.1 Emma C. Thomson, Ph.D., MRCP1 Kate Templeton, Ph.D.2 Rory N. Gunson, FRCPath3 E. Carol McWilliam Leitch, Ph.D.1 1MRC-University of Glasgow Centre for Virus Research, Glasgow, UK 2Edinburgh Specialist Virology Centre, Edinburgh, UK 3West of Scotland Specialist Virology Centre, Glasgow, UK
Antenatal Diagnosis of Fetal Genotype Determines if Maternal Hyperglycemia Due to a Glucokinase Mutation Requires Treatment
Authors: Ali J. Chakera, Victoria L. Carleton, Sian Ellard, Jencia Wong, Dennis K. Yue, Jason Pinner, Andrew T. Hattersley, Glynis P. Ross
Journal: Diabetes Care (2012)

In women with hyperglycemia due to heterozygous glucokinase (GCK) mutations, the fetal genotype determines its growth. If the fetus inherits the mutation, birth weight is normal when maternal hyperglycemia is not treated, whereas intensive treatment may adversely reduce fetal growth. However, fetal genotype is not usually known antenatally, making treatment decisions difficult.We report two women with gestational diabetes mellitus resulting from GCK mutations with hyperglycemia sufficient to merit treatment.In both women, DNA from chorionic villus sampling, performed after high-risk aneuploidy screening, showed the fetus had inherited the GCK mutation. Therefore, maternal hyperglycemia was not treated. Both offspring had a normal birth weight and no peripartum complications.In pregnancies where the mother has hyperglycemia due to a GCK mutation, knowing the fetal GCK genotype guides the management of maternal hyperglycemia. Fetal genotyping should be performed when fetal DNA is available from invasive prenatal diagnostic testing.
Prognostic relevance of a novel semiquantitative classification of Bcl2 immunohistochemical expression in human infiltrating ductal carcinomas of the breast
Authors: D. Treré, L. Montanaro, C. Ceccarelli, S. Barbieri, G. Cavrini, D. Santini, M. Taffurelli, M. Derenzini
Journal: Annals of Oncology (2007)
Definitive Chemoradiotherapy for T4 and/or M1 Lymph Node Squamous Cell Carcinoma of the Esophagus
Authors: Atsushi Ohtsu, Narikazu Boku, Kei Muro, Keisho Chin, Manabu Muto, Shigeaki Yoshida, Mitsuo Satake, Satoshi Ishikura, Takashi Ogino, Yoshinori Miyata, Shigeki Seki, Kazuhiro Kaneko, Akira Nakamura
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To investigate the efficacy and feasibility of concurrent chemoradiotherapy for locally advanced carcinoma of the esophagus. PATIENTS AND METHODS: Fifty-four patients with clinically T4 and/or M1 lymph node (LYM) squamous cell carcinoma of the esophagus were enrolled. Patients received protracted infusion of fluorouracil 400 mg/m 2 /24 hours on days 1 to 5 and 8 to 12, 2-hour infusion of cisplatin 40 mg/m 2 on days 1 and 8, and concurrent radiation therapy at a dose of 30 Gy in 15 fractions over 3 weeks. Filgrastim was prophylactically administered to 35 patients. This schedule was repeated twice every 5 weeks, for a total radiation dose of 60 Gy, followed by two courses of fluorouracil (800 mg/m 2 /24 hours for 5 days) and cisplatin (80 mg/m 2 on day 1). RESULTS: There were 21 patients with T4M0 disease, one with T2M1 LYM, 17 with T3M1 LYM, and 15 withT4M1 LYM. Forty-nine patients (91%) completed at least the chemoradiotherapy segment. The 18 patients (33%) who achieved a complete response included nine (25%) of the 36 with T4 disease and nine (50%) of the 18 with non-T4 disease. Major toxicities were leukocytopenia and esophagitis; there were four (7%) treatment-related deaths. Prophylactic filgrastim reduced the incidence of grade 3 or worse leukopenia without improving dose-intensity or response. With a median follow-up duration of 43 months, median survival time was 9 months. The 3-year survival rate was 23%. CONCLUSION: Despite its significant toxicity, this combined modality seemed to have curative potential even in cases of locally advanced carcinoma of the esophagus.
T Cell Antigen Receptor Recognition of Antigen-Presenting Molecules
Authors: Jamie Rossjohn, Stephanie Gras, John J. Miles, Stephen J. Turner, Dale I. Godfrey, James McCluskey
Journal: Annual Review of Immunology (2014)

The Major Histocompatibility Complex (MHC) locus encodes classical MHC class I and MHC class II molecules and nonclassical MHC-I molecules. The architecture of these molecules is ideally suited to capture and present an array of peptide antigens (Ags). In addition, the CD1 family members and MR1 are MHC class I–like molecules that bind lipid-based Ags and vitamin B precursors, respectively. These Ag-bound molecules are subsequently recognized by T cell antigen receptors (TCRs) expressed on the surface of T lymphocytes. Structural and associated functional studies have been highly informative in providing insight into these interactions, which are crucial to immunity, and how they can lead to aberrant T cell reactivity. Investigators have determined over thirty unique TCR-peptide-MHC-I complex structures and twenty unique TCR-peptide-MHC-II complex structures. These investigations have shown a broad consensus in docking geometry and provided insight into MHC restriction. Structural studies on TCR-mediated recognition of lipid and metabolite Ags have been mostly confined to TCRs from innate-like natural killer T cells and mucosal-associated invariant T cells, respectively. These studies revealed clear differences between TCR-lipid-CD1, TCR-metabolite-MR1, and TCR-peptide-MHC recognition. Accordingly, TCRs show remarkable structural and biological versatility in engaging different classes of Ag that are presented by polymorphic and monomorphic Ag-presenting molecules of the immune system.
Leishmania promastigotes selectively inhibit interleukin 12 induction in bone marrow-derived macrophages from susceptible and resistant mice.
Authors: L Carrera, R T Gazzinelli, R Badolato, S Hieny, W Muller, R Kuhn, D L Sacks
Journal: The Journal of Experimental Medicine (1996)

Leishmania major promastigotes were found to avoid activation of mouse bone marrow-derived macrophages (BMM0) in vitro for production of cytokines that are typically induced during infection with other intracellular pathogens. Coexposure of BMM0 to the parasite and other microbial stimuli resulted in complete inhibition of interleukin (IL) 12 (p40) mRNA induction and IL-12 release. In contrast, mRNA and protein levels for IL-1(alpha), IL-1(beta), tumor necrosis factor (TNF) alpha, and inducible NO synthase (iNOS) were only partially reduced, and signals for IL-10 and monocyte chemoattractant protein (MCP-1/JE) were enhanced. The parasite could provide a detectable trigger for TNF-alpha and iNOS in BMM0 primed with interferon (IFN) gamma, but still failed to induce IL-12. Thus IL-12 induction is selectively impaired after infection, whereas activation pathways for other monokine responses remain relatively intact. Selective and complete inhibition of IL-12(p40) induction was observed using BMM0 from either genetically susceptible or resistant mouse strains, as well as IL-10 knockout mice, and was obtained using promastigotes from cutaneous, visceral, and lipophosphoglycan-deficient strains of Leishmania. The impaired production of the major physiological inducer of IFN-gamma is suggested to underlie the relatively prolonged interval of parasite intracellular survival and replication that is typically associate with leishmanial infections, including those producing self-limiting disease.
Percutaneous tibial nerve stimulation versus sham electrical stimulation for the treatment of faecal incontinence in adults (CONFIDeNT): a double-blind, multicentre, pragmatic, parallel-group, randomised controlled trial
Authors: Charles H Knowles, Emma J Horrocks, Stephen A Bremner, Natasha Stevens, Christine Norton, P Ronan O'Connell, Sandra Eldridge
Journal: The Lancet (2015)
Codon Usage in Mitochondrial Genomes: Distinguishing Context-Dependent Mutation from Translational Selection
Authors: W. Jia, P. G. Higgs
Journal: Molecular Biology and Evolution (2007)

We analyze the frequencies of synonymous codons in animal mitochondrial genomes, focusing particularly on mammals and fish. The frequencies of bases at 4-fold degenerate sites are found to be strongly influenced by context-dependent mutation, which causes correlations between pairs of neighboring bases. There is a pattern of excess of certain dinucleotides and deficit of others that is consistent across large numbers of species, despite the wide variation of single-nucleotide frequencies among species. In many bacteria, translational selection is an important influence on codon usage. In order to test whether translational selection also plays a role in mitochondria, we need to control for context-dependent mutation. Selection for translational accuracy can be detected by comparison of codon usage in conserved and variable sites in the same genes. We give a test of this type that works in the presence of context-dependent mutation. There is very little evidence for translational accuracy selection in the mitochondrial genes considered here. Selection for translational efficiency might lead to preference for codons that match the limited repertoire of anticodons on the mitochondrial tRNAs. This is difficult to detect because the effect would usually be in the same direction in comparable to codon families and so would not cause an observable difference in codon usage between families. Several lines of evidence suggest that this type of selection is weak in most cases. However, we found several cases where unusual bases occur at the wobble position of the tRNA, and in these cases, some evidence for selection on codon usage was found. We discuss the way that these unusual cases are associated with codon reassignments in the mitochondrial genetic code.
Simvastatin Blunts Endotoxin-Induced Tissue Factor In Vivo
Authors: Sabine Steiner, Walter S. Speidl, Johannes Pleiner, Daniela Seidinger, Gerlinde Zorn, Christoph Kaun, Johann Wojta, Kurt Huber, Erich Minar, Michael Wolzt, Christoph W. Kopp
Journal: Circulation (2005)

Beyond lipid lowering, various antiinflammatory properties have been ascribed to statins. Moreover, in vitro studies have suggested the presence of anticoagulant effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, as lipopolysaccharide (LPS)-induced monocyte tissue factor (TF) was suppressed. In this study, we examined the role of statins in experimental endotoxemia on inflammatory and procoagulant responses in vivo.In this double-blind, placebo-controlled, parallel-group study, 20 healthy, male subjects were randomized to receive either simvastatin (80 mg/d) or placebo for 4 days before intravenous administration of LPS (20 IU/kg IV). Plasma high-sensitive C-reactive protein (hsCRP), monocyte chemoattractant protein (MCP-1), sCD40L, sCD40, and prothrombin fragment F1+2 (F1.2) were determined by ELISAs at baseline and at 4 and 8 hours after LPS administration. Monocyte TF expression and monocyte-platelet aggregates were measured by whole-blood flow cytometry over the same time course. The increases in hsCRP and MCP-1, both known inducers of TF, were significantly suppressed by statin treatment after LPS challenge. Statin premedication blunted the increase of monocyte TF expression in response to LPS. In parallel, endotoxin-induced formation of F1.2 was significantly reduced by simvastatin after 4 and 8 hours. LPS infusion affected neither the formation and activation of monocyte-platelet aggregates nor plasma levels of sCD40 and sCD40L.Simvastatin suppresses the inflammatory response to endotoxin and blunts monocyte TF expression but does not affect platelet activation.
Long-term cultures of murine fetal liver retain very early B lymphoid phenotype.
Authors: K A Denis, L J Treiman, J I St Claire, O N Witte
Journal: The Journal of Experimental Medicine (1984)

Long-term cultures of murine fetal liver have been successfully established using a modification of our in vitro bone marrow culture system (14, 15). Fetal liver cells from midgestation BALB/c embryos were plated onto BAB-14 bone marrow stromal cell-adherent layers. After a 3-5 wk period, cell growth began to increase and these cells were expanded in number on fresh feeder layers. The cultured fetal liver cells were lymphoid in morphology, 5-20% cytoplasmic Ig-positive, but less than 1% surface Ig-positive. Southern blot analysis of the cultured fetal liver cells, as well as cultured bone marrow-derived B cells, demonstrated a population with germline Ig heavy chain loci, possibly representing very early B cell precursors. Abelson murine leukemia virus (A-MuLV) clonal transformants of such cultured fetal liver cells had a phenotypic distribution similar to that seen with fresh fetal liver transformants but distinct from those obtained with the transformation of either cultured or fresh bone marrow. All A-MuLV transformants isolated had rearrangements at the mu heavy chain locus of both chromosomes, irrespective of Ig production. In addition, most mu heavy chain producers had at least one rearranged kappa gene locus. These long-term fetal liver cultures provide large numbers of cells for studying events early in the B lymphocyte lineage. The cultured fetal liver cells retained phenotypic traits similar to fresh fetal liver B cells and distinctive from bone marrow cells cultured under similar conditions.
URINARY EXCRETION OF TRYPTOPHAN METABOLITES BY SCHIZOPHRENIC INDIVIDUALS
Authors: F. CHRISTINE BROWN, J. B. WHITE, J. K. KENNEDY
Journal: American Journal of Psychiatry (1960)

Urine from schizophrenic patients and normal controls has been analyzed for metabolites of tryptophan, before and after oral doses of this compound. With the exception of the basal excretion of N-methyl-2-pyridone-5-carboxamide, no significant differences in the urinary excretions of tryptophan metabolites has been found.
Reducing global health inequalities. Part 1
Authors: Kenneth Stuart, EJL Soulsby
Journal: Journal of the Royal Society of Medicine (2011)

This paper summarizes four UK reviews of socially stratified health inequalities that were undertaken during the past five decades. It describes the background of misplaced optimism and false hopes which characterized the UK's own record of health inequalities; the broken promises on debt cancellations which was the experience of developing countries. It describes why the UK's past leadership record in international health provides grounds for optimism for the future and for benefits for both developed and developing countries through the adoption of more collaborative approaches to global health than have characterized international relationships in the past. It recalls the enthusiasm generated in the UK, and internationally, by the establishment of the Global Commission on the Social Determinants of Health. It promotes the perception of health both as a global public good and as a developmental issue and why a focus on poverty is essential to the address of global health issues. It sees the designing of appropriate strategies and partnerships towards the achievement of the Millennium Development Goals as an important first step for achieving successful address to global public health issues.
A rat model of the cognitive impairment from Pfiesteria piscicida exposure.
Authors: E D Levin
Journal: Environmental Health Perspectives (2001)

Pfiesteria piscicida Steidinger & Burkholder, an estuarine dinoflagellate known to kill fish, has also been associated with neurocognitive deficits in humans. We have developed a rat model to determine the cause-and-effect relationship between exposure to Pfiesteria-containing water and cognitive impairment and to determine the neurobehavioral mechanisms underlying the Pfiesteria effect. The rat model of Pfiesteria toxicity can also provide important information concerning the toxin or toxins responsible for neurocognitive deficits resulting from Pfiesteria exposure. With the rat model we have repeatedly documented a Pfiesteria-induced choice accuracy impairment during radial-arm maze learning. The Pfiesteria-induced impairment was relatively specific to the acquisition phase of training. When rats were pretrained, Pfiesteria treatment did not affect performance. However, when these same rats were retrained on another task, the Pfiesteria-induced impairment became evident. Pfiesteria-induced effects were also seen in a locomotor activity test in the figure-8 apparatus and selected components of the functional observational battery. Pfiesteria effects on choice accuracy in the radial-arm maze in rats constitute a critical component of the model of Pfiesteria toxicity, as the hallmark of Pfiesteria toxicity in humans is cognitive dysfunction. Our finding that analysis of the first six sessions of radial-arm maze testing is sufficient for determining the effect means that this test will be useful as a rapid screen for identifying the critical neurotoxin(s) of Pfiesteria in future studies.
A CASE OF MENINGOCELE
Authors: B. P. Pick
Journal: BMJ (1929)

THE BRIT1S over the dull area, but occasionally, a sound suggestive of an intestinal gurgle was heard.The, diagnosis of a diaphragmatic hernia was made, and the child sent to the x-ray room for confirmation 6f the-diagnosis.A barium meal showed the stomach 'to be normial 'and in its usual position, but the left ltng was collapsed into the apex of the leftpleural cavity.A second radiogram (Fig. 3) showed the gas-filled colon and intestinies in the pleural cavity.The patient was given glucose and sodium bicarbonate,by the rectum to lower acidosis and prepare him for operation.Operation.An oblique incision was made fro'm the ninth intercostal space downwards and forwards *to the umbilicus.The upper-part of
Juvenile idiopathic arthritis associated with autoimmune hepatitis type 2
Authors: V Nobili
Journal: Annals of the Rheumatic Diseases (2004)

No patient had a history of a male twin or a solid organ transplant at the time of biopsy.SLE, systemic lupus erythematosus; CLE, cutaneous lupus erythematosus; DM, dermatomyositis; MF, mycosis fungoides.
Molecular basis of von Willebrand disease type IIB. Candidate mutations cluster in one disulfide loop between proposed platelet glycoprotein Ib binding sequences.
Authors: A M Randi, I Rabinowitz, D J Mancuso, P M Mannucci, J E Sadler
Journal: Journal of Clinical Investigation (1991)

Many variants of von Willebrand disease (vWD) with qualitatively abnormal von Willebrand factor (vWF) are recognized. In vWD type IIB, the abnormal protein displays enhanced affinity for a platelet vWF receptor, the glycoprotein Ib-IX complex. 14 patients from 7 unrelated families with vWD type IIB were studied to determine the molecular basis for this phenotype. Specific oligonucleotide primers were used to amplify portions of vWF exon 28 encoding a domain that interacts with the platelet glycoprotein Ib-IX complex. Candidate missense mutations were identified for all 14 patients by DNA sequencing, allele specific oligonucleotide hybridization, and restriction endonuclease digestion. These sequence changes occur in an 11 amino acid segment within a single disulfide loop bounded by Cys(509) and Cys(695). All of these sequence changes are C----T transitions within CG dinucleotides. Six patients from two unrelated families were heterozygous for the encoded sequence Arg(543)----Trp. Seven patients from four unrelated families were heterozygous for the encoded sequence Arg(545)----Cys; this sequence change appears to have occurred independently three times, once as a new spontaneous mutation. One patient with apparently sporadic vWD type IIB was heterozygous for the encoded sequence Val(553)----Met, and this appears to be a new mutation. None of these sequence changes was found in 100 normal alleles. These findings suggest that vWD type IIB may be caused by relatively few distinct mutations, that these mutations may cluster within a specific region of one disulfide loop in vWF domain A1, and that this region can modulate the affinity of vWF for the platelet glycoprotein Ib-IX complex.
Importance of recruitment of bone marrow-derived CXCR4+ cells in post-infarct cardiac repair mediated by G-CSF
Authors: Y MISAO, G TAKEMURA, M ARAI, T OHNO, H ONOGI, T TAKAHASHI, S MINATOGUCHI, T FUJIWARA, H FUJIWARA
Journal: Cardiovascular Research (2006)

Objective: Granulocyte-colony stimulating factor (G-CSF) accelerates repair following myocardial infarction (MI). Recently, the beneficial effects of post-MI administration of G-CSF were reported to be mediated by direct activation of the Jak–Stat pathway in cardiomyocytes. Our aim was to test the hypothesis that bone marrow-derived cells recruited into the infarcted myocardium are the primary mediators of the beneficial effects by G-CSF.