tbuckley/cabot-search huggingface dataset:
Novel antiplasmodial agents
Authors: Mei‐Lin Go
Journal: Medicinal Research Reviews (2003)

The morbidity and mortality associated with malaria have spurred efforts to find novel antimalarial agents with improved potency and selectivity. Leads for agents continue to be obtained from natural sources (plants and microorganisms) and chemical syntheses. Screening of commercial or specialized databases have also yielded promising leads. The structural diversity of compounds with good (micromolar and lower) activity point to the considerable tolerance for different structural elements in the "antimalarial pharmacophore." It may also be a reflection of the varied targets present in the plasmodia. The challenge in malaria chemotherapy is to find safe and selective agents whose potencies will not be compromised by plasmodial resistance. Modification of potential leads should also aim at improving "drug-like" character, viz. to ensure acceptable oral bioavailability. A review of the literature shows that there is a growing trend towards the development of target-specific antimalarial agents (for example, agents inhibiting plasmodial farnesyl transferase, cyclin dependent kinases, proteases, choline transport). An increasing number of reports focus on the development of chemosensitizers, agents that are capable of reversing plasmodial resistance.
Active Surveillance for Low-Risk Prostate Cancer Worldwide: The PRIAS Study
Authors: Meelan Bul, Xiaoye Zhu, Riccardo Valdagni, Tom Pickles, Yoshiyuki Kakehi, Antti Rannikko, Anders Bjartell, Deric K. van der Schoot, Erik B. Cornel, Giario N. Conti, Egbert R. Boevé, Frédéric Staerman, Jenneke J. Vis-Maters, Henk Vergunst, Joris J. Jaspars, Petra Strölin, Erik van Muilekom, Fritz H. Schröder, Chris H. Bangma, Monique J. Roobol
Journal: European Urology (2012)
Safer primary care for all: a global imperative
Authors: Aziz Sheikh, Sukhmeet S Panesar, Itziar Larizgoitia, David W Bates, Liam J Donaldson
Journal: The Lancet Global Health (2013)

2is intended to help redress this imbalance by signifying WHO’s intention to stimulate international action to support the delivery of safer primary care. This begs the question of why, more than a decade after the issue was raised, so little progress has been made in primary care. 3 This situation can partly be explained by the fact that the fi ndings from original studies showing the high frequency of medical errors and associated morbidity were all undertaken in hospital settings. 4 These landmark epidemiological investigations fi rst alerted the international community to key areas of concern in hospital care provision and resulted in a range of government-backed policy and research initiatives, 5
Plasma marinobufagenin-like and ouabain-like immunoreactivity during saline volume expansion in anesthetized dogs
Authors: A. Y. Bagrov, O. V. Fedorova, R. I. Dmitriev, A. W. French, D. E. Anderson
Journal: Cardiovascular Research (1996)

This study investigated effects of acute plasma volume expansion on plasma levels and urinary output of two endogenous Na,K-ATPase inhibitors, marinobufagenin-like and ouabain-like immunoreactive substances.Plasma volume was expanded for 3 h via intravenous saline infusion in three groups of anesthetized dogs--nontreated (n = 5); pretreated with rabbit antidigoxin (n = 5); and pretreated with rabbit antimouse (control) antibody (n = 4).Plasma marinobufagenin-like immunoreactivity increased to 11.87 +/- 3.16 nmol.l-1 (vs. 0.30 +/- 0.16 nmol.l-1) within 10 min of volume expansion, in parallel with a 15% increase in LVdP/dt, then decreased to 2.21 +/- 0.59 nmol.l-1, and in 90 min increased to 11.8 +/- 2.8 nmol.l-1, in parallel with the maximal natriuretic response. Plasma concentrations of ouabain-like immunoreactive material were increased after 90 min of saline infusion (0.019 +/- 0.004 nmol.l-1 vs. 0.139 +/- 0.056 nmol.l-1). Pretreatment of the animals with antidigoxin antibody blocked the positive inotropic and reduced natriuretic response to volume expansion, and decreased the urinary release of marinobufagenin-like, but not ouabain-like, material.These results show the presence of marinobufagenin-like immunoreactive substance in dog plasma and suggest that mammalian EDLF may have a bufodienolide nature. Endogenous marinobufagenin-like immunoreactive substance, which is likely to cross-react with antidigoxin antibody, is involved in the natriuretic and positive inotropic responses to plasma volume expansion.
Sublethal gamma-radiation induces differentiation of CD4-/CD8- into CD4+/CD8+ thymocytes without T cell receptor beta rearrangement in recombinase activation gene 2-/- mice.
Authors: J C Zúñiga-Pflücker, D Jiang, P L Schwartzberg, M J Lenardo
Journal: The Journal of Experimental Medicine (1994)

DNA recombination of the immunoglobulin (Ig) or T cell receptor (TCR) gene loci is an essential step in the production of lymphocytes bearing antigen-specific receptors. Mice that lack the ability to rearrange their Ig and TCR gene loci are devoid of mature B and T cells. Complete rearrangement and expression of the TCR-beta chain has been suggested to allow immature thymocytes to switch from the CD4-/CD8- to the CD4+/CD8+ stage of thymic development. Thus, thymocytes from severe combined immune deficient (SCID) mice or mice deficient in recombinase activation genes (RAG), which do not undergo proper DNA rearrangement, are arrested at the early CD4-/CD8- stage of development. B cell precursors in SCID or RAG mice do not progress from the B220+/sIgM-/heat stable antigen (HSA)+/CD43+ to the B220+/sIgM-/HSA+/CD43- stage. In an attempt to reconstitute RAG-2-/- mice with bone marrow- or fetal liver-derived progenitor cells, we subjected these mice to sublethal doses of gamma-radiation. It is surprising that in the absence of donor cells, irradiated RAG-2-/- mice revealed a dramatic change in their lymphoid phenotype. 14 d after irradiation, the majority of thymocytes had advanced to the CD4+/CD8+ stage of T cell development and a small number of bone marrow precursors had progressed to the CD43-, HSAhi stage of B cell development. Analysis of the resulting CD4+/CD8+ thymocytes revealed no surface expression of the TCR/CD3 complex and no V-D-J rearrangement of the TCR-beta gene locus. Our findings provide evidence for a novel pathway that allows the transition of thymocytes from the CD4-/CD8- to the CD4+/CD8+ stage and that does not appear to require TCR-beta chain rearrangement.
Integrating Mortality and Morbidity Outcomes
Authors: Niall D. Ferguson, Damon C. Scales, Ruxandra Pinto, M. Elizabeth Wilcox, Deborah J. Cook, Gordon H. Guyatt, Holger J. Schünemann, John C. Marshall, Margaret S. Herridge, Maureen O. Meade
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Outcome measures that integrate mortality and morbidity, like quality-adjusted life years (QALYs), have been proposed for critical care clinical trials.We sought to describe the distribution of QALYs in critically ill patients and estimate sample size requirements for a hypothetical trial using QALYs as the primary outcome.We used data from a prospective cohort study of survivors of acute respiratory distress syndrome to generate utility values and calculate QALYs at 6 and 12 months. Using multiple simulations, we estimated the required sample sizes for multiple outcome scenarios in a hypothetical trial, including a base-case wherein the intervention improved both mortality and QALYs among survivors.From 195 enrolled patients, follow-up was sufficient to generate QALY outcomes for 168 (86.2%) at 6 months and 159 (81.5%) at 1 year. For a hypothetical intervention that reduced mortality from 48 to 44% and improved QALYs by 0.025 in survivors at 6 months, the required per-group sample size was 571 (80% power; two-sided α = 0.05), compared with 2,436 patients needed for a comparison focusing on mortality alone. When only mortality or QALY in survivors (but not both) showed improvement by these amounts, 3,426 and 1,827 patients per group were needed, respectively. When mortality and morbidity effects moved in opposite directions, simulation results became impossible to interpret.QALYs may be a feasible outcome in critical care trials yielding a patient-centered result and major gains in statistical power under certain conditions, but this approach is susceptible to several threats, including loss to follow-up.
Conduction Block Associated with Transient Depolarizations Induced by Acetylstrophanthidin in Isolated Canine Purkinje Fibers
Authors: JAMES H. SOUNDERS, GREGORY R. FERRIER, GORDON K. MOE
Journal: Circulation Research (1973)

Transient depolarizations (TDs) appeared in canine Purkinje tissue but not in cardiac muscle during exposure to 1-2 x 10 -7 g/ml of acetylstrophanthidin. At low levels of toxicity, the TDs were associated with a decrease in threshold and an increase in automaticity. As intoxication progressed, the TDs coincided with transient periods of increased threshold and conduction block. Propagation from muscle to Purkinje tissue was blocked during, but not before or after, the crest of the TDs. As a result of the interaction between temporal and spatial (electrotonic) factors, various patterns of block, including unidirectional block, were observed. At moderate frequencies 2:1 block was demonstrated, but at faster rates 1:1 transmission occurred. At a later stage of toxicity, repetitive stimulation led to progressive depolarization in Purkinje tissue followed by a period of block during which slow repolarization eventually restored excitability and conductivity. In the whole heart, conduction block could permit reentry and could be responsible for the ultimate transition from ventricular tachycardia to ventricular fibrillation.
Acute Severe Asthma
Authors: E. R. McFadden
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Acute severe asthma remains a major economic and health burden. The natural history of acute decompensations is one of resolution and only about 0.4% of patients succumb overall. Mortality in medical intensive care units is higher but is less than 3% of hospital admissions. "Near-fatal" episodes may be more frequent, but precise figures are lacking. However, about 30% of medical intensive care unit admissions require intubation and mechanical ventilation with mortality of 8%. Morbidity and mortality increase with socioeconomic deprivation and ethnicity. Seventy to 80% of patients in emergency departments clear within 2 hours with standardized care. The relapse rate varies between 7 and 15%, depending on how aggressively the patient is treated. The airway obstruction in the 20-30% of people resistant to adrenergic agonists in the emergency department slowly reverses over 36-48 hours but requires intense treatment to do so. Current therapeutic options for this group consist of ipratropium and corticosteroids in combination with beta2 selective drugs. Even so, such regimens are not optimal and better approaches are needed. The long-term prognosis after a near-fatal episode is poor and mortality may approach 10%.
A Novel Low Molecular Weight Inhibitor of Dendritic Cells and B Cells Blocks Allergic Inflammation
Authors: Peter Ettmayer, Peter Mayer, Frank Kalthoff, Wolfgang Neruda, Nathalie Harrer, Gabriella Hartmann, Michelle M. Epstein, Volker Brinkmann, Christoph Heusser, Maximilian Woisetschläger
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

During allergic lung inflammation dendritic cells (DCs) direct the generation and function of effector T-helper type 2 cells. T-helper type 2 cells not only orchestrate the inflammatory processes in the tissue by inducing the accumulation and activation of proinflammatory cells but also induce IgE production by B cells. Thus, inhibitors of DC function should have therapeutic benefits in patients with allergies.VAF347, a novel low molecular weight immunomodulator, is described and acts as an antiinflammatory compound by a dual mode of action.VAF347 inhibited the function of human monocyte-derived DCs to induce T-cell proliferation and cytokine production. Mechanistically, this effect may be due to reduced expression of CD86, HLA-DR, and interleukin 6 by DCs. In addition, the compound inhibited IgE synthesis in an isotype-specific fashion by human B lymphocytes. In a mouse model of antigen-induced eosinophilic inflammation, VAF347 blocked lung eosinophilia, mucus hyperplasia, and serum IgE levels, representing the hallmarks of allergic lung inflammation. The biological effects in vivo are most likely mediated by the immunoregulatory role of VAF347 on DCs because allergic lung inflammation was also inhibited in B-cell-deficient mice.VAF347 represents a novel type of immunomodulator by affecting two major pathways in allergic airway pathogenesis: dendritic cell-mediated T-helper-cell activation and induction of IgE production by human B lymphocytes.
Differential distribution of haematopoietic and nonhaematopoietic progenitor cells in intralesional and extralesional keloid: do keloid scars provide a niche for nonhaematopoietic mesenchymal stem cells?
Authors: S.A. Iqbal, F. Syed, D.A. McGrouther, R. Paus, A. Bayat
Journal: British Journal of Dermatology (2010)

Background Keloid disease is a benign, quasineoplastic disease with a high recurrence rate. Mesenchymal‐like stem cells (MLSC) have previously been demonstrated in keloid scars and may be involved in keloid pathobiology. However, as these cells have only been examined by single colour fluorescence activated cell sorting (FACS) alone, they need to be more comprehensively characterized so that the key cellular contributors to keloid scars can be better understood. Objectives To identify and characterize MLSC in intralesional and extralesional keloid, and to distinguish haematopoietic stem cells (HSC) from mesenchymal stem cells (MSC). Methods and patients Punch biopsies from intralesional (top, middle and margin) and extralesional keloid scar sites were obtained from 17 patients with a keloid. Multicolour FACS analysis using antibodies specific for HSC markers CD34 and CD117 and MSC markers CD13, CD29, CD44 and CD90 was performed on freshly isolated keloid scar cells and on passage 0 and 1 cells. This was complemented by real‐time quantitative polymerase chain reaction (PCR) and immunohistological in situ analyses. Results Keloid scars contain distinct subpopulations of MLSCs. Cells positive for CD13, CD29, CD44 and CD90 were found to be significantly (P <0·05) higher in the top and middle compartments of keloid scars compared with extralesional skin, where cells positive for CD34, CD90 and CD117 (representing HSCs) predominated. A unique population of CD34+ cells (cells positive for CD13, CD29, CD34, CD44 and CD90) were found in keloid scars and in extralesional skin. FACS and quantitative PCR analysis showed that many of the MSC markers were progressively downregulated and all HSC markers were lost during extended keloid fibroblast culture up to passage 1. Conclusion We have found distinct subpopulations of haematopoietic and nonhaematopoietic MSC in keloid scars, whereby HSC accumulate extralesionally, while keloids seem to provide a niche environment for nonhaematopoietic MSC. Future therapy of keloids may have to target differentially both stem cell populations in order to deprive these tumours of their regenerative cell pools.
Prediction of oral appliance efficiency in patients with apnoea using phrenic nerve stimulation while awake
Authors: V. Bosshard, J.-F. Masse, F. Series
Journal: Thorax (2011)

Background In patients with sleep apnoea, primary oropharyngeal collapse of the upper airway during sleep is an important predictor of treatment success with an oral appliance. Phrenic nerve stimulation is able to induce upper airway obstruction and was therefore used to mimic the target for an efficient treatment with an oral appliance. Objective To test if the site(s) of upper airway collapse identified by means of bilateral anterior magnetic stimulation during wakefulness could predict the efficacy of treatment with an oral appliance in patients with obstructive sleep apnoea. Methods The site(s) of upper airway collapse while awake were identified by examining the flow–pressure relationship of flow-limited twitches when measuring velopharyngeal and oropharyngeal pressure. Once the mandibular advancement titration had been completed, the efficacy of mandibular advancement was documented during an in-lab sleep study. Results 33 patients (24 men and 9 women, apnoea–hypopnoea index (AHI) 32.5±17.1/h) participated in the study. Flow limitation was obtained in 29, but 3 of these had no follow-up sleep study with the device. Subjects with oropharyngeal and velopharyngeal collapse did not differ in the phenotypic characteristics associated with a positive response to an oral appliance (gender, apnoea severity, body mass index or positional dependency of breathing disturbances). Complete or partial success was seen in 14/17 subjects with twitch-induced oropharyngeal collapse and in 4/12 patients with velopharyngeal closure. Treatment response was significantly different in subjects with twitch-induced oropharyngeal and velopharyngeal collapse (OR 9.5, 95% CI 1.6 to 52.7). Conclusions Identifying the site of upper airway collapse by using bilateral anterior magnetic stimulation of the phrenic nerve during wakefulness can predict treatment success with an oral appliance in patients with sleep apnoea.
Tumor necrosis factor downregulates an endothelial nitric oxide synthase mRNA by shortening its half-life.
Authors: M Yoshizumi, M A Perrella, J C Burnett, M E Lee
Journal: Circulation Research (1993)

Nitric oxide (NO), which accounts for the biological properties of endothelium-derived relaxing factor, is generated by NO synthase (NOS). The vascular endothelium contains two types of NOS: one is constitutively expressed (cNOS), and the other is inducible. Endothelium-mediated vasorelaxation is impaired in atherosclerotic vessels. To determine whether tumor necrosis factor (TNF)-alpha, which is commonly found in atherosclerotic lesions, has an effect on NOS message, we measured cNOS mRNA levels in TNF-treated human umbilical vein endothelial cells (HUVECs) by RNA blot analysis with a cNOS cDNA probe. TNF-alpha markedly reduced cNOS mRNA levels in HUVECs in a dose- and time-dependent manner. In response to 3 ng/mL TNF-alpha, cNOS mRNA levels began to decrease at 4 hours and diminished to only 5% of control levels at 24 hours. As little as 0.1 ng/mL TNF-alpha reduced cNOS mRNA levels by 50%. This reduction in cNOS message in response to TNF-alpha depended on protein synthesis as it was blocked by cycloheximide. In nuclear runoff experiments, TNF-alpha did not change the rate of cNOS gene transcription. cNOS mRNA is very stable under basal conditions, with a half-life of 48 hours; however, treatment with TNF-alpha shortened this half-life to 3 hours. TNF-alpha thus appears to decrease cNOS mRNA levels by increasing the rate of mRNA degradation. TNF-induced reductions in cNOS mRNA levels may have an important effect on impaired endothelium-mediated vasorelaxation in atherosclerosis.
Systems biology of bacteriophage proteins and new dimensions of the virus world discovered through metagenomics
Authors: David M Kristensen, Arcady R Mushegian, Eugene V Koonin
Journal: Genome biology (2011)

Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations.We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders.Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation.We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population.The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of proteincoding variation and the diff erential signatures of population structure from rare and common variation.This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health.
Increased Vascular Senescence and Impaired Endothelial Progenitor Cell Function Mediated by Mutation of Circadian Gene <i>Per2</i>
Authors: Chao-Yung Wang, Ming-Shien Wen, Hong-Wei Wang, I-Chang Hsieh, Yuxin Li, Ping-Yen Liu, Fun-Chung Lin, James K. Liao
Journal: Circulation (2008)

Alteration of the circadian rhythm and increased vascular senescence are linked to cardiovascular disease. Per2, a circadian gene, is known to regulate endothelium-dependent vasomotion. However, the mechanism by which Per2 affects endothelial function is unknown. We hypothesize that endothelial dysfunction in Per2 mutant (Per2(m/m)) mice is mediated in part by increased vascular senescence and impaired endothelial progenitor cell (EPC) function.Endothelial cells from Per2(m/m) mice exhibit increased protein kinase Akt signaling, greater senescence, and impaired vascular network formation and proliferation. Indeed, Per2(m/m) mice have impaired blood flow recovery and developed autoamputation of the distal limb when subjected to hind-limb ischemia. Furthermore, matrigel implantation into Per2(m/m) mice resulted in less neovascularization. Because EPCs contribute to angiogenesis, we studied the role of Per2 in these cells using bone marrow transplantation. Basal EPC levels were similar between wild-type and Per2(m/m) mice. However, compared with wild-type bone marrow transplantation mice, EPC mobilization was impaired in Per2(m/m) bone marrow transplantation mice in response to ischemia or VEGF stimulation. Bone marrow transplantation or infusion of wild-type EPC restored blood flow recovery and prevented autoamputation in Per2(m/m) mice.These findings indicate that mutation of Per2 causes Akt-dependent senescence and impairs ischemia-induced revascularization through the alteration of EPC function.
Identification of non-coding RNAs embracing microRNA-143/145 cluster
Authors: Akio Iio, Yoshihito Nakagawa, Ichiro Hirata, Tomoki Naoe, Yukihiro Akao
Journal: Molecular Cancer (2010)

In a variety of cancers, altered patterns of microRNA (miRNA) expression are reported and may affect the cell cycle and cell survival. Recent studies suggest that the expression level of miRNAs that act as tumor suppressors is frequently reduced in cancers because of chromosome deletions, epigenetical changes, aberrant transcription and disturbances in miRNA processing. miR-143 and -145, which are located approximately 1.3 kb from each other at chromosome 5q33, are highly expressed in several tissues, but down-regulated in most cancers. However, the mechanism of this down-regulation has not been investigated in detail. Here, we show that both miRNAs were expressed well under the same control program in human tissues, but were down-regulated equally in the most of the cancer cell lines tested. Then we identified the host gene encoding both miRNAs. The transcripts of this gene were approximately 11, 7.5, and 5.5 kb long; and the expression of these transcripts was coordinated with that of its resident miRNAs and down-regulated in the cancer cell lines tested as well as in colorectal cancer tissue samples. These data demonstrate that the host gene can function as a primary miRNA transcript and suggest that the down-regulation of host gene expression caused the low-expression of its encoded microRNAs-143 and -145 in human cancer cell lines and in cancer tissues.