tbuckley/cabot-search huggingface dataset:
The cortical reaction and development of activation competence in mammalian oocytes
Authors: T Ducibella
Journal: Human Reproduction Update (1996)

Blocks to polyspermic fertilization are necessary to prevent the incorporation of two sperm nuclei into a zygote's genome, which would result in abnormal development. Many mammalian eggs utilize both an extracellular zona pellucida block to polyspermy and a plasma membrane block. Although little is known about the plasma membrane block in mammals, fertilization results in zona glycoprotein modifications caused by enzymes released by the egg and its cortical granules (CG). This article reviews other recent investigations demonstrating that the oocyte's ability to cause CG release and the block to polyspermy develops near the time of ovulation. The development of normal 'activation competence' is likely to involve preovulatory changes in the oocyte's ability to signal the release of intracellular calcium as well as to respond to this calcium increase, resulting in CG exocytosis. Because normal activatin competence appears to have a brief temporal window after oocyte meiotic maturation is resumed and since the oocytes are collected at various stages in assisted reproductive procedures, these studies are relevant to optimizing clinical success. Keywords: activation competence/calcium/cortical granules/in-vitro fertilization/oocyte maturation
Mutation-Selection Models of Codon Substitution and Their Use to Estimate Selective Strengths on Codon Usage
Authors: Z. Yang, R. Nielsen
Journal: Molecular Biology and Evolution (2008)

Current models of codon substitution are formulated at the levels of nucleotide substitution and do not explicitly consider the separate effects of mutation and selection. They are thus incapable of inferring whether mutation or selection is responsible for evolution at silent sites. Here we implement a few population genetics models of codon substitution that explicitly consider mutation bias and natural selection at the DNA level. Selection on codon usage is modeled by introducing codon-fitness parameters, which together with mutation-bias parameters, predict optimal codon frequencies for the gene. The selective pressure may be for translational efficiency and accuracy or for fine-tuning translational kinetics to produce correct protein folding. We apply the models to compare mitochondrial and nuclear genes from several mammalian species. Model assumptions concerning codon usage are found to affect the estimation of sequence distances (such as the synonymous rate dS, the nonsynonymous rate dN, and the rate at the 4-fold degenerate sites d4), as found in previous studies, but the new models produced very similar estimates to some old ones. We also develop a likelihood ratio test to examine the null hypothesis that codon usage is due to mutation bias alone, not influenced by natural selection. Application of the test to the mammalian data led to rejection of the null hypothesis in most genes, suggesting that natural selection may be a driving force in the evolution of synonymous codon usage in mammals. Estimates of selection coefficients nevertheless suggest that selection on codon usage is weak and most mutations are nearly neutral. The sensitivity of the analysis on the assumed mutation model is discussed.
Rosuvastatin and Cardiovascular Events in Patients Undergoing Hemodialysis
Authors: Bengt C. Fellström, Alan G. Jardine, Roland E. Schmieder, Hallvard Holdaas, Kym Bannister, Jaap Beutler, Dong-Wan Chae, Alejandro Chevaile, Stuart M. Cobbe, Carola Grönhagen-Riska, José J. De Lima, Robert Lins, Gert Mayer, Alan W. McMahon, Hans-Henrik Parving, Giuseppe Remuzzi, Ola Samuelsson, Sandor Sonkodi, Gultekin Süleymanlar, Dimitrios Tsakiris, Vladimir Tesar, Vasil Todorov, Andrzej Wiecek, Rudolf P. Wüthrich, Mattis Gottlow, Eva Johnsson, Faiez Zannad
Journal: New England Journal of Medicine (2009)

Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not been proved.We conducted an international, multicenter, randomized, double-blind, prospective trial involving 2776 patients, 50 to 80 years of age, who were undergoing maintenance hemodialysis. We randomly assigned patients to receive rosuvastatin, 10 mg daily, or placebo. The combined primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary end points included death from all causes and individual cardiac and vascular events.After 3 months, the mean reduction in low-density lipoprotein (LDL) cholesterol levels was 43% in patients receiving rosuvastatin, from a mean baseline level of 100 mg per deciliter (2.6 mmol per liter). During a median follow-up period of 3.8 years, 396 patients in the rosuvastatin group and 408 patients in the placebo group reached the primary end point (9.2 and 9.5 events per 100 patient-years, respectively; hazard ratio for the combined end point in the rosuvastatin group vs. the placebo group, 0.96; 95% confidence interval [CI], 0.84 to 1.11; P=0.59). Rosuvastatin had no effect on individual components of the primary end point. There was also no significant effect on all-cause mortality (13.5 vs. 14.0 events per 100 patient-years; hazard ratio, 0.96; 95% CI, 0.86 to 1.07; P=0.51).In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. (ClinicalTrials.gov number, NCT00240331.)
Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study
Authors: R. Buhl, C. Gessner, W. Schuermann, K. Foerster, C. Sieder, S. Hiltl, S. Korn
Journal: Thorax (2015)

<h3>Background</h3> QVA149 is a once-daily (o.d.) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β<sub>2</sub>-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD. The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol (TIO+FOR) in improving health-related quality of life (HRQoL) of patients with COPD. <h3>Methods</h3> This multicentre, blinded, triple-dummy, parallel-group, non-inferiority study randomised patients aged ≥40 years with moderate-to-severe COPD (post-bronchodilator forced expiratory volume in 1 s (FEV<sub>1</sub>) ≥30% to &lt;80% predicted) to QVA149 110/50 µg o.d. or TIO 18 µg o.d.+ FOR 12 µg twice daily (1:1) for 26 weeks. The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George9s Respiratory Questionnaire-COPD (SGRQ-C). The prespecified non-inferiority margin was 4 units. Secondary endpoints included Transition Dyspnoea Index (TDI) score, pre-dose FEV<sub>1</sub>, forced vital capacity (FVC) and safety. <h3>Results</h3> Of the 934 patients randomised (QVA149=476 and TIO+FOR=458), 87.9% completed the study. At week 26, non-inferiority was met for SGRQ-C (QVA149 vs TIO+FOR; difference: –0.69 units; 95% CI −2.31 to 0.92; p=0.399). A significantly higher percentage of patients achieved a clinically relevant ≥1 point improvement in TDI total score with QVA149 (49.6%) versus TIO+FOR (42.4%; p=0.033). QVA149 significantly increased pre-dose FEV<sub>1</sub> (+68 mL, 95% CI 37 mL to 100 mL; p&lt;0.001) and FVC (+74 mL, 95% CI 24 mL to 125 mL; p=0.004) compared with TIO+FOR at week 26. The incidence of adverse events was comparable between both treatments (QVA149=43.7% and TIO+FOR=42.6%). <h3>Conclusions</h3> QVA149 is non-inferior to TIO+FOR in improving HRQoL, with clinically meaningful and significant improvements in breathlessness and lung function in patients with COPD. <h3>Trial registration number</h3> NCT01120717.
Characteristics and Clinical Significance of Angiographically Mild Lesions in Acute Coronary Syndromes
Authors: Sorin J. Brener, Gary S. Mintz, Ecaterina Cristea, Giora Weisz, Akiko Maehara, John A. McPherson, Steven P. Marso, Naim Farhat, Hans Erik Botker, Ovidiu Dressler, Ke Xu, Barry Templin, Zhen Zhang, Alexandra J. Lansky, Bernard de Bruyne, Patrick W. Serruys, Gregg W. Stone
Journal: JACC. Cardiovascular imaging (2012)
Insulin-Dependent Activation of Endothelial Nitric Oxide Synthase Is Impaired by O-Linked Glycosylation Modification of Signaling Proteins in Human Coronary Endothelial Cells
Authors: Massimo Federici, Rossella Menghini, Alessandro Mauriello, Marta Letizia Hribal, Francesca Ferrelli, Davide Lauro, Paolo Sbraccia, Luigi Giusto Spagnoli, Giorgio Sesti, Renato Lauro
Journal: Circulation (2002)

Hyperglycemia impairs functional properties of cytosolic and nuclear proteins via O-linked glycosylation modification (O-GlcNAcylation). We studied the effects of O-GlcNAcylation on insulin signaling in human coronary artery endothelial cells.O-GlcNAcylation impaired the metabolic branch of insulin signaling, ie, insulin receptor (IR) activation of the IR substrate (IRS)/phosphatidylinositol 3-kinase (PI3-K)/Akt, whereas it enhanced the mitogenic branch, ie, ERK-1/2 and p38 (mitogen-activated protein kinase). Both in vivo and in vitro phosphorylation of endothelial nitric oxide synthase (eNOS) by Akt were reduced by hyperglycemia and hexosamine activation. Insulin-induced eNOS activity in vivo was reduced by hyperglycemia and hexosamine activation, which was coupled to increased activation and expression of matrix metalloproteinase-2 and -9; these phenomena were reversed by inhibition of the hexosamine pathway. Finally, carotid plaques from type 2 diabetic patients showed increased endothelial O-GlcNAcylation with respect to nondiabetics.Our data show that hyperglycemia, through the hexosamine pathway, impairs activation of the IR/IRS/PI3-K/Akt pathway, resulting in deregulation of eNOS activity.
Potential significance of physiological and pharmacological glucocorticoids in early pregnancy
Authors: A. E. Michael, A. T. Papageorghiou
Journal: Human Reproduction Update (2008)

Despite extensive studies of the developmental consequences of increased glucocorticoid exposure in mid- to late pregnancy, relatively little is known regarding the significance of glucocorticoids in early pregnancy. The objective of this review was to consider potential roles for this family of corticosteroids that might relate to early pregnancy. Although this is a narrative review, 249 source articles addressing potential effects of glucocorticoids on aspects of early pregnancy and development (published between 1997 and 2007) were identified using a systematic literature search. Additional articles (115) were identified if cited by the primary reference articles identified in the systematic phase of the review. Much of the evidence to implicate glucocorticoids in early pregnancy comes from studies of steroid receptors and the 11β-hydroxysteroid dehydrogenase enzymes, which modulate cortisol action in the endometrium/decidua, trophoblast, placenta and embryo/fetus. The evidence reviewed suggests that in early pregnancy the actions of glucocorticoids are balanced between positive effects that would promote pregnancy (e.g. stimulation of hCG secretion, suppression of uterine natural killer cells, and promotion of trophoblast growth/invasion) versus adverse effects that would be expected to compromise the pregnancy (e.g. inhibition of cytokine-prostaglandin signalling, restriction of trophoblast invasion following up-regulation of plasminogen activation inhibitor-1, induction of apoptosis, and inhibition of embryonic and placental growth). Glucocorticoids exert many actions that could impact both negatively and positively on key aspects of early pregnancy. These steroids may also be implicated in obstetric complications, including intra-uterine growth restriction, pre-term labour, pre-eclampsia and chorio-aminionitis.
Structure of idiotopes associated with antiphenylarsonate antibodies expressing an intrastrain crossreactive idiotype.
Authors: S Haba, M B Lascombe, R J Poljak, A Nisonoff
Journal: The Journal of Experimental Medicine (1989)

We have explored the structural basis of idiotopes associated with the major idiotype (CRIA) of A/J anti-p-azobenzenearsonate antibodies, with emphasis on the regions of contact with anti-idiotypic antibody. The analysis was facilitated by a recent description of the three-demensional structure of the Fab portion of a CRIA-related antibody molecule. Direct binding measurements failed to reveal idiotopes associated exclusively with the L chain. However, the L chain participated in the formation of approximately 80% of the idiotopes recognized by polyclonal anti-Id. This indicates that multiple complementarity-determining regions (CDRs) participate in the formation of idiotopes. The affinity of anti-Id for CDRs on L chains must be appreciable but insufficient to permit direct binding (i.e., less than approximately 10(4) M-1). Approximately 20-35% of polyclonal anti-Id reacted with high affinity with H chains recombined with non-CRIA-related L chains. This interaction was found to involve the D region as well as one or both CDRs in the VH segment, again indicating the contribution of multiple CDRs. It is suggested that a typical idiotope may be similar in size to that of protein epitopes whose three-dimensional structures are known; such epitopes comprise a substantial fraction of the surface area occupied by the CDRs of an antibody. The expression of an idiotope recognized by the mAb AD8, which interacts with the VH segment, was found to be unaffected by major changes in the neighboring D and VL regions. This observation is relevant to efforts to predict three-dimensional structure from the amino acid sequence of CRIA+ molecules.
Should Data from Demographic Surveillance Systems Be Made More Widely Available to Researchers?
Authors: Daniel Chandramohan, Kenji Shibuya, Philip Setel, Sandy Cairncross, Alan D Lopez, Christopher J. L Murray, Basia Żaba, Robert W Snow, Fred Binka
Journal: PLoS Medicine (2008)

Demographic surveillance--the process of monitoring births, deaths, causes of deaths, and migration in a population over time--is one of the cornerstones of public health research, particularly in investigating and tackling health disparities. An international network of demographic surveillance systems (DSS) now operates, mostly in sub-Saharan Africa and Asia. Thirty-eight DSS sites are coordinated by the International Network for the Continuous Demographic Evaluation of Populations and Their Health (INDEPTH). In this debate, Daniel Chandramohan and colleagues argue that DSS data in the INDEPTH database should be made available to all researchers worldwide, not just to those within the INDEPTH Network. Basia Zaba and colleagues argue that the major obstacles to DSS sites sharing data are technical, managerial, and financial rather than proprietorial concerns about analysis and publication. This debate is further discussed in this month's Editorial.
Genomic resolution of an aggressive, widespread, diverse and expanding meningococcal serogroup B, C and W lineage
Authors: Jay Lucidarme, Dorothea M.C. Hill, Holly B. Bratcher, Steve J. Gray, Mignon du Plessis, Raymond S.W. Tsang, Julio A. Vazquez, Muhamed-Kheir Taha, Mehmet Ceyhan, Adriana M. Efron, Maria C. Gorla, Jamie Findlow, Keith A. Jolley, Martin C.J. Maiden, Ray Borrow
Journal: Journal of Infection (2015)
Hepatitis C virus and hepatocarcinogenesis
Authors: Soung Won Jeong, Jae Young Jang, Raymond T. Chung
Journal: Clinical and Molecular Hepatology (2012)

Hepatitis C virus (HCV) is an RNA virus that is unable to integrate into the host genome. However, its proteins interact with various host proteins and induce host responses. The oncogenic process of HCV infection is slow and insidious and probably requires multiple steps of genetic and epigenetic alterations, the activation of cellular oncogenes, the inactivation of tumor suppressor genes, and dysregulation of multiple signal transduction pathways. Stellate cells may transdifferentiate into progenitor cells and possibly be linked to the development of hepatocellular carcinoma (HCC). Viral proteins also have been implicated in several cellular signal transduction pathways that affect cell survival, proliferation, migration and transformation. Current advances in gene expression profile and selective messenger RNA analysis have improved approach to the pathogenesis of HCC. The heterogeneity of genetic events observed in HCV-related HCCs has suggested that complex mechanisms underlie malignant transformation induced by HCV infection. Considering the complexity and heterogeneity of HCCs of both etiological and genetic aspects, further molecular classification is required and an understanding of these molecular complexities may provide the opportunity for effective chemoprevention and personalized therapy for HCV-related HCC patients in the future. In this review, we summarize the current knowledge of the mechanisms of hepatocarcinogenesis induced by HCV infection. Keywords: Hepatitis C virus; Hepatocellular carcinoma; Molecular
Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy
Authors: Anne Angelillo-Scherrer, Laurent Burnier, Nathalie Flores, Pierre Savi, Maria DeMol, Paul Schaeffer, Jean-Marc Herbert, Greg Lemke, Stephen P. Goff, Glenn K. Matsushima, H. Shelton Earp, Christian Vesin, Marc F. Hoylaerts, Stéphane Plaisance, Désiré Collen, Edward M. Conway, Bernhard Wehrle-Haller, Peter Carmeliet
Journal: Journal of Clinical Investigation (2005)

Mechanisms regulating thrombus stabilization remain largely unknown. Here, we report that loss of any 1 of the Gas6 receptors (Gas6-Rs), i.e., Tyro3, Axl, or Mer, or delivery of a soluble extracellular domain of Axl that traps Gas6 protects mice against life-threatening thrombosis. Loss of a Gas6-R does not prevent initial platelet aggregation but impairs subsequent stabilization of platelet aggregates, at least in part by reducing "outside-in" signaling and platelet granule secretion. Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the β3 integrin, thereby amplifying outside-in signaling via αIIbβ3. Blocking the Gas6-R–αIIbβ3 integrin cross-talk might be a novel approach to the reduction of thrombosis.
Mortality of the Ambulance Ride
Authors: F. G. C. Strange
Journal: BMJ (1967)

110 mm.Hg.She was confused with paranoid trends, and exhibited hallucinations at times.-Depression had also been noted by her relatives before she was admitted to hospital.Physical examination showed osteoarthritis of both knee joints and small joints of the hands, confirmed by x-ray.Intravenous pyelogram showed normal appearance of both kidneys.Her haemoglobin was 6 g./100 ml. and the blood picture was hypochromic and microcytic, which improved after iron therapy.Blood sugar, electro- lytes, proteins, and cholesterol were normal.There was no glycosuria, and urinary 17-ketosteroid estimation was within normal limits.X- ray of the skull showed well-marked hyperostosis frontalis interna (Fig. 1).As seen in Figs. 2 and3, obesity was mainly limited to the upper arms and thighs.Association of hirsutism, obesity, and hyperostosis frontalis interna has been observed under the tide of " Stewart-Morel Syndrome " or " Morgagni-Morel Syndrome."Morel reported 17 cases and Stewart reported a few cases.'Michaux described a case in 1959 presenting mental symptoms along with this syndrome.'
The unfolding of therapeutic radiology
Authors: J A del Regato
Journal: JAMA (1989)

In September 1926, I registered for basic medical studies at the University of Havana (Cuba). In exchange for serving as a scribe in the admission office, I was given room and board in the interns' quarters of the 2000-bed university hospital. Within 3 weeks, a hurricane hit Havana dead center; thousands were killed and many more injured. The flow of casualties was overwhelming and all hands were needed. I learned to place tourniquets and to give ether anesthesia. Blood transfusions required the presence of a qualified donor and were done arm to arm with large syringes. In the aftermath of the hurricane, I was assigned as a male nurse's aide to apply dressings and give injections in the dermatology pavilion. Professor Pardo-Castelló came early to do his rounds and, in the absence of his interns, I followed him with the order book. In the process, he taught me a lot.
Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine
Authors: P. M. Izmirly, M. Y. Kim, C. Llanos, P. U. Le, M. M. Guerra, A. D. Askanase, J. E. Salmon, J. P. Buyon
Journal: Annals of the Rheumatic Diseases (2010)

<h3>Background</h3> Based on the potential involvement of Toll-like receptor (TLR) signalling in the pathogenesis of neonatal lupus (NL), it was hypothesised that fetal exposure to hydroxychloroquine (HCQ), a TLR inhibitor, might reduce the risk of anti-SSA/Ro/SSB/La antibody-associated cardiac manifestations of NL (cardiac-NL). <h3>Methods</h3> Cardiac-NL children (N=50) and controls (N=151) were drawn from the following overlapping pregnancy studies: Research Registry for NL; PR Interval and Dexamethasone Evaluation in Cardiac-NL; and Predictors of Pregnancy Outcomes: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus (SLE). Pregnancies met the following inclusion criteria: documentation of maternal anti-SSA/Ro/SSB/La antibodies at pregnancy, confirmation of medication use and child9s outcome, a diagnosis of SLE before pregnancy and birth by 31 December 2007. <h3>Results</h3> Seven (14%) of the cardiac-NL children were exposed to HCQ compared with 56 (37%) of the controls (p=0.002; OR 0.28; 95% CI 0.12 to 0.63). Cases and controls were similar with respect to demographic and antibody status. Multivariable analysis adjusting for birth year, maternal race/ethnicity, antibody status, non-fluorinated steroid use and prior cardiac-NL risk yielded an OR associated with HCQ use of 0.46 (95% CI 0.18 to 1.18; p=0.10). <h3>Conclusion</h3> This case–control study suggests that, in mothers with SLE with anti-SSA/Ro/SSB/La antibodies, exposure to HCQ during pregnancy may decrease the risk of fetal development of cardiac-NL. Prospective studies are needed for confirmation.