tbuckley/cabot-search huggingface dataset:
NLRP3 inflammasome activation results in hepatocyte pyroptosis, liver inflammation, and fibrosis in mice
Authors: Alexander Wree, Akiko Eguchi, Matthew D. McGeough, Carla A. Pena, Casey D. Johnson, Ali Canbay, Hal M. Hoffman, Ariel E. Feldstein
Journal: Hepatology (2013)

Inflammasome activation plays a central role in the development of drug-induced and obesity-associated liver disease. However, the sources and mechanisms of inflammasome-mediated liver damage remain poorly understood. Our aim was to investigate the effect of NLRP3 inflammasome activation on the liver using novel mouse models. We generated global and myeloid cell-specific conditional mutant Nlrp3 knock-in mice expressing the D301N Nlrp3 mutation (ortholog of D303N in human NLRP3 ), resulting in a hyperactive NLRP3. To study the presence and significance of NLRP3-initiated pyroptotic cell death, we separated hepatocytes from nonparenchymal cells and developed a novel flow-cytometry–based (fluorescence-activated cell sorting; FACS) strategy to detect and quantify pyroptosis in vivo based on detection of active caspase 1 (Casp1)- and propidium iodide (PI)-positive cells. Liver inflammation was quantified histologically by FACS and gene expression analysis. Liver fibrosis was assessed by Sirius Red staining and quantitative polymerase chain reaction for markers of hepatic stellate cell (HSC) activation. NLRP3 activation resulted in shortened survival, poor growth, and severe liver inflammation; characterized by neutrophilic infiltration and HSC activation with collagen deposition in the liver. These changes were partially attenuated by treatment with anakinra, an interleukin-1 receptor antagonist. Notably, hepatocytes from global Nlrp3-mutant mice showed marked hepatocyte pyroptotic cell death, with more than a 5-fold increase in active Casp1/PI double-positive cells. Myeloid cell-restricted mutant NLRP3 activation resulted in a less-severe liver phenotype in the absence of detectable pyroptotic hepatocyte cell death. Conclusions : Our data demonstrate that global and, to a lesser extent, myeloid-specific NLRP3 inflammasome activation results in severe liver inflammation and fibrosis while identifying hepatocyte pyroptotic cell death as a novel mechanism of NLRP3-mediated liver damage. (HEPATOLOGY 2014;59:898–910)
Obesity in middle age is an independent risk factor for cardiovascular disease
Authors: Susan Mayor
Journal: BMJ (2006)

Obesity during middle age in people who do not have high blood pressure or high cholesterol concentrations increases their risk in old age of hospitalisation or death from coronary heart disease, cardiovascular disease, or diabetes. This is the conclusion of a large prospective study published this week that compared obese people with normal weight people who had similar cardiovascular risks.

Obesity is already known to be associated with a higher risk of cardiovascular disease and death, but the study set out to determine whether it has an additional effect on cardiovascular outcomes independently of its strong associations with established coronary risk factors, including high blood pressure and high cholesterol concentrations. The study followed 17 643 men and women aged from 31 …
No role for CXCL12–G801A polymorphism in the development of extramedullary disease in acute myeloid leukemia
Authors: V Ponziani, F Mannelli, N Bartalucci, G Gianfaldoni, F Leoni, E Antonioli, P Guglielmelli, S Ciolli, A Bosi, A M Vannucchi
Journal: Leukemia (2007)
Intramuscular vitamin K and childhood cancer: Authors' reply
Authors: J Golding, R Greenwood, M Mott
Journal: BMJ (1992)

and delivered non-spontaneously and children given oral vitamin K or no vitamin K and delivered spontaneously.An appropriate way to separate any possible effect of type of delivery from the effect of vitamin K would be a Mantel-Haenszel analysis in which the data are stratified also for type of delivery (or a logistic regression analysis using a model that incorporates interaction terms between the variables hospital and type of delivery, as well as between hospital and year of delivery).
Idoxuridine in Herpes Simplex Virus (Type 1) Encephalitis
Authors: DAVID C. NOLAN
Journal: Annals of Internal Medicine (1973)

We studied 29 patients with herpes simplex virus, type 1, encephalitis in Michigan between 1966 and 1971. Twenty patients were treated intravenously with idoxuridine at doses of up to 86 mg/kg body weight per day for 5 days. Overall mortality (among patients surviving for 48 hours after hospitalization) in the treated and supportive groups was 33%. Mortality was greatest in patients over 50 years of age (67%). However, 9 of the 12 idoxuridine-treated survivors are well today, whereas 1 of the 6 nontreated living patients is well. If 54 mg/kg body weight of idoxuridine is given intravenously for 5 days in two divided, rapid infusions (50 mg/min), pharmacologic effects are maximal and toxicity minimal. No patient should be given a total dose of more than 20 g of idoxuridine.
Quantities of lead producing health effects in humans: sources and bioavailability.
Authors: K R Mahaffey
Journal: Environmental Health Perspectives (1977)

Levels of lead ingestion and inhalation producing increased body burden of lead and clinical toxicity in adults and children are compared with usual levels of exposure. The magnitude of lead exposure from air, water, and food is estimated. Sources of high level exposure to lead are described; urban street dirt, house dust, and paint are particularly common sources of high concentrations of lead. The bioavailability of different lead compounds is reviewed as well as factors affecting susceptibility to lead.
Osteoclast-specific cathepsin K deletion stimulates S1P-dependent bone formation
Authors: Sutada Lotinun, Riku Kiviranta, Takuma Matsubara, Jorge A. Alzate, Lynn Neff, Anja Lüth, Ilpo Koskivirta, Burkhard Kleuser, Jean Vacher, Eero Vuorio, William C. Horne, Roland Baron
Journal: Journal of Clinical Investigation (2013)

Cathepsin K (CTSK) is secreted by osteoclasts to degrade collagen and other matrix proteins during bone resorption. Global deletion of Ctsk in mice decreases bone resorption, leading to osteopetrosis, but also increases the bone formation rate (BFR). To understand how Ctsk deletion increases the BFR, we generated osteoclast- and osteoblast-targeted Ctsk knockout mice using floxed Ctsk alleles. Targeted ablation of Ctsk in hematopoietic cells, or specifically in osteoclasts and cells of the monocyte-osteoclast lineage, resulted in increased bone volume and BFR as well as osteoclast and osteoblast numbers. In contrast, targeted deletion of Ctsk in osteoblasts had no effect on bone resorption or BFR, demonstrating that the increased BFR is osteoclast dependent. Deletion of Ctsk in osteoclasts increased their sphingosine kinase 1 (Sphk1) expression. Conditioned media from Ctsk-deficient osteoclasts, which contained elevated levels of sphingosine-1-phosphate (S1P), increased alkaline phosphatase and mineralized nodules in osteoblast cultures. An S1P1,3 receptor antagonist inhibited these responses. Osteoblasts derived from mice with Ctsk-deficient osteoclasts had an increased RANKL/OPG ratio, providing a positive feedback loop that increased the number of osteoclasts. Our data provide genetic evidence that deletion of CTSK in osteoclasts enhances bone formation in vivo by increasing the generation of osteoclast-derived S1P.
IL-13 induces eosinophil recruitment into the lung by an IL-5– and eotaxin-dependent mechanism
Authors: Samuel M. Pope, Eric B. Brandt, Anil Mishra, Simon P. Hogan, Nives Zimmermann, Klaus I. Matthaei, Paul S. Foster, Marc E. Rothenberg
Journal: Journal of Allergy and Clinical Immunology (2001)
Born selfish? Rationality, altruism, and the initial state
Authors: Margery Lucas, Laura Wagner
Journal: Behavioral and Brain Sciences (2005)

Henrich et al. propose that humans are genetically equipped with learning mechanisms that enable them to acquire the preferences and beliefs related to economic prosocial behaviors. In addition to their cross-cultural data, they cite developmental evidence in support of this theory. We challenge Henrich et al.'s interpretation of the developmental data in a discussion of recent work which suggests that preferences for altruism and fairness may have an innate basis.
Inhibitory Role of Plasminogen Activator Inhibitor-1 in Arterial Wound Healing and Neointima Formation
Authors: Peter Carmeliet, Lieve Moons, Roger Lijnen, Stefaan Janssens, Florea Lupu, Désiré Collen, Robert D. Gerard
Journal: Circulation (1997)

Background Plasminogen-deficient mice display impaired vascular wound healing and reduced arterial neointima formation after arterial injury, suggesting that inhibition of plasmin generation might reduce arterial neointima formation. Therefore, we studied the consequences of plasminogen activator inhibitor-1 (PAI-1) gene inactivation and adenoviral PAI-1 gene transfer on arterial neointima formation. Methods and Results Neointima formation was evaluated in PAI-1–deficient (PAI-1 −/− ) mice with perivascular electric or transluminal mechanical injury. PAI-1 deficiency improved vascular wound healing in both models: the cross-sectional neointimal area was 0.001±0.001 mm 2 in PAI-1 +/+ and 0.016±0.008 mm 2 in PAI-1 −/− mice within 1 week after electric injury ( P &lt;.02) and 0.055±0.008 mm 2 in PAI-1 +/+ and 0.126±0.006 mm 2 in PAI-1 −/− mice within 3 weeks after mechanical injury ( P &lt;.001). Proliferation of smooth muscle cells was not affected by PAI-1 deficiency. Topographic analysis of arterial wound healing after electric injury revealed that PAI-1 −/− smooth muscle cells, originating from the uninjured borders, more rapidly migrated into the necrotic center of the arterial wound than wild-type smooth muscle cells. On the basis of immunostaining, PAI-1 expression was markedly upregulated during vascular wound healing. There were no genotypic differences in reendothelialization of the vascular wound. When PAI-1 −/− mice were intravenously injected with replication- defective adenovirus expressing human PAI-1 (AdCMVPAI-1), plasma PAI-1 antigen levels increased in a dose-dependent fashion up to to 61±8 μg/mL with 2×10 9 plaque-forming units (pfu) virus. Luminal stenosis was 35±13% in control AdRR5-treated (2×10 9 pfu) and suppressed to 5±5% in AdCMVPAI-1–treated (6×10 8 pfu) PAI-1 −/− mice ( P &lt;.002). Conclusions By affecting cellular migration, PAI-1 plays an inhibitory role in vascular wound healing and arterial neointima formation after injury, and adenoviral PAI-1 gene transfer reduces arterial neointima formation in mice.
Egress of CD19+CD5+ cells into peripheral blood following treatment with the Bruton tyrosine kinase inhibitor ibrutinib in mantle cell lymphoma patients
Authors: Betty Y. Chang, Michelle Francesco, Martin F. M. De Rooij, Padmaja Magadala, Susanne M. Steggerda, Min Mei Huang, Annemieke Kuil, Sarah E. M. Herman, Stella Chang, Steven T. Pals, Wyndham Wilson, Adrian Wiestner, Marcel Spaargaren, Joseph J. Buggy, Laurence Elias
Journal: Blood (2013)
Health bill should include commitment to promote medical research, say research leaders
Authors: Z. Kmietowicz
Journal: BMJ (2011)

UK research leaders have backed calls for the integration of hospital and community health services, public health, and social care as the way to improve healthcare, rather than restructuring of the service in England as proposed by the health secretary, Andrew Lansley, in his health reform bill.

They also believe that a duty to support and promote medical research should be enshrined in the bill because it could translate into better care for patients and help pay off the country’s debts by boosting the drug industry. They urge that, to champion research, Sally Davies, the chief medical officer for England and head of the National Institute for Health Research, be given a seat on the NHS Commissioning Board, which will oversee the …
Smoking and intermediate alpha1-antitrypsin deficiency and lung function in middle-aged men.
Authors: C Larsson, S Eriksson, H Dirksen
Journal: BMJ (1977)

Lung function was evaluated in a representative population sample of 50-year-0ld men living in one Swedish city. Twenty-four smoking and 15 non-smoking men heterozygous for alpha1-antitrypsin deficiency--that is, with the protease-inhibitor (Pi1 phenotype MZ--were carefully matched for weight and smoking habit with Pi M controls. The pulmonary function of non-smoking Pi MZ subjects did not differ from that of non-smoking Pi M controls. In contrast, smoking heterozygotes showed a significant loss of elastic recoil, enlarged residual volumes, and increased closing capacity but no signs of obstructive ventilatory impairment. Most smoking Pi MZ individuals reported mild exertional dyspnoea.
Procedural Skills Training in Internal Medicine Residencies
Authors: Robert Swift Wigton, L. L. Blank, J. A. Nicolas, Thomas Gerald Tape
Journal: Annals of Internal Medicine (1989)

To obtain the opinions of internal medicine residency program directors about which procedural skills residents master during training and the amount of training needed to attain and maintain competence in each procedure.A mailed survey to all program directors in the United States.Program directors or their designees from 389 of 431 (90%) internal medicine residency programs.For several procedures, 40% more respondents said all residents should master the procedure than said all their residents do master the procedure. Some procedures commonly done in practice were perceived as mastered by all residents in fewer than half of the programs. There were few differences in procedures learned by size or type of program. A fellowship program did affect exposure to some procedures in the field covered by the program. Median recommendations of training needed to master each procedure were similar to those of practicing internists for most procedures.Current residency training does not assure competency in all of the procedures the general internist does in practice. Program directors should examine which skills are adequately taught, test competence, and ways to improve residents' skills. Practicing general internists should have access to supervised training in procedural skills.
Haloethylene-related compounds of industrial, environmental, and medical significance
Authors: Herbert S. Posner, Hans L. Falk
Journal: Environmental Health Perspectives (1977)

A broad-based literature survey was made for chemicals that contain either a haloethylene or a related substructure. Two hundred and sixty-two compounds, including synthetic intermediates, pesticides, solvents, drugs, food components, natural products, and metabolites, are grouped by their structures. Some are in current use or are bioavailable while little exposure is expected from others. As more biologic-response information is reported for small compounds of these types, it should become possible to select others for research on additional questions of structure-activity relationships. Some of the compounds are widespread while others are not. Some are used or found in large amounts while others may be trace contaminants, minor or more major by-products of synthesis or isolation. The pesticides and solvents, for example, are knowingly and often deliberately released to the environment, sometimes in very large quantities. Inadvertent release also occurs, sometimes referred to as fugitive emission. Food contaminants and drugs are directly accessible to humans. Sparsely distributed natural products could be accessible to humans, for example, via the food chain. Some of the compounds in food may be formed during preparation, storage or metabolically. Last, the haloethylene function has often been synthesized into compounds in order to achieve desired biologic activities. There are many types and degrees of relatedness of structure, depending upon atomic dimensions and stereochemical, polar, resonance, and other factors. Furthermore, for some chemical series, biologic responses are continuously variable while, in other cases, it is not uncommon that qualitatively different types of response occur with apparently very close homologs. Genetic, metabolic, and behavioral factors affecting response must also be considered. Thus, safety or hazard cannot yet be predicted conclusively by apparent relatedness of structure alone. Also, since the tables are noncomprehensive, some relevant compounds have likely been omitted. The haloalkanes, for example, are not here because of their large number, despite the knowledge that some are either metabolized or nonbiologically converted to haloalkenes.
Sublingual varices are not unusual
Authors: Michael N Pemberton
Journal: BMJ (2006)

Editor-Walker et al show convincingly that drivers and other occupants of heavy four wheel drive vehicles are safer in crashes than those in smaller or lighter vehicles and those on foot or cycle. 1 They also show that drivers of these vehicles use mobile phones more often and seat belts less often than drivers of other cars.But by conflating mobile phone use (which distracts drivers) and non-use of seat belts (which makes drivers feel less safe) as equally important examples of illegal and dangerous practices they have sown confusion and undermined the prospect of a constructive approach to road safety.Using mobile phones and not using seatbelts have opposing consequences for other road users.The distraction caused by mobile phones increases the threat to others, but the non-use of seat belts decreases it.As the authors note, deaths of pedestrians, cyclists, and rear seat passengers increased (by 8%, 13%, and 28% respectively) after laws mandating the use of seat belts in front seats were introduced in the United Kingdom.
Induction of murine liver damage by overexpression of CD40 ligand provides an experimental model to study fulminant hepatic failure
Authors: Volker Schmitz, Frank Dombrowski, Jesús Prieto, Cheng Qian, Linda Diehl, Percy Knolle, Tilman Sauerbruch, Wolfgang H. Caselmann, Ulrich Spengler, Ludger Leifeld
Journal: Hepatology (2006)

Previously, we demonstrated that intrahepatic upregulation of the immunoactivating molecules CD40 and CD40 ligand (CD40L) are early mechanisms for liver cell damage in human and murine fulminant hepatic failure (FHF). In the present study, we investigated the functional effects of intrahepatic overexpression of CD40L by adenoviral-mediated gene transfer (AdCD40L) in mice. AdCD40L injection induced severe liver cell damage, which was associated with increased alanine aminotransferase (ALT) levels peaking at day 5 after vector administration (AdCD40L, 1,707 +/- 279 U/L; AdLacZ, 213 +/- 25 U/L) and with lethality in half of the mice. Except for mild splenomegaly, no organs other than the liver were involved in inflammatory reactions. CD40-CD40L interaction was mandatory for liver damage, because CD40(-/-) mice were completely protected. Furthermore, CD40L-induced FHF depended on competent lymphocytes, because inflammatory reactions were strongly decreased in SCID and Rag1(-/-) mice. In contrast, neither natural killer T (NKT) cells nor Kupffer cells relevantly influenced histology as shown in NKT cell-deficient CD1d(-/-) mice and by gadolinium depletion of Kupffer cells. Furthermore, immunosuppression by dexamethasone and cyclosporin A was not sufficient to block CD40L damage. In conclusion, we present a model of FHF with strong similarities to human FHF with respect to time course and histological changes. This model suggests involvement of the CD40-CD40L system in FHF and might have important implications for future pathophysiological studies of this condition.
Guidelines for Antisense Oligonucleotide Design and Insight Into Splice-modulating Mechanisms
Authors: Annemieke Aartsma-Rus, Laura van Vliet, Marscha Hirschi, Anneke AM Janson, Hans Heemskerk, Christa L de Winter, Sjef de Kimpe, Judith CT van Deutekom, Peter AC 't Hoen, Gert-Jan B van Ommen
Journal: Molecular Therapy (2008)

Antisense oligonucleotides (AONs) can interfere with mRNA processing through RNase H-mediated degradation, translational arrest, or modulation of splicing. The antisense approach relies on AONs to efficiently bind to target sequences and depends on AON length, sequence content, secondary structure, thermodynamic properties, and target accessibility. We here performed a retrospective analysis of a series of 156 AONs (104 effective, 52 ineffective) previously designed and evaluated for splice modulation of the dystrophin transcript. This showed that the guanine-cytosine content and the binding energies of AON-target and AON-AON complexes were significantly higher for effective AONs. Effective AONs were also located significantly closer to the acceptor splice site (SS). All analyzed AONs are exon-internal and may act through steric hindrance of Ser-Arg-rich (SR) proteins to exonic splicing enhancer (ESE) sites. Indeed, effective AONs were significantly enriched for ESEs predicted by ESE software programs, except for predicted binding sites of SR protein Tra2beta, which were significantly enriched in ineffective AONs. These findings compile guidelines for development of AONs and provide more insight into the mechanism of antisense-mediated exon skipping. On the basis of only four parameters, we could correctly classify 79% of all AONs as effective or ineffective, suggesting these parameters can be used to more optimally design splice-modulating AONs.
The alteration of superoxide dismutase, catalase, glutathione peroxidase, and NAD(P)H cytochrome c reductase in guinea pig polymorphonuclear leukocytes and alveolar macrophages during hyperoxia.
Authors: M Rister, R L Baehner
Journal: Journal of Clinical Investigation (1976)

Superoxide dismutase, catalase, glutathione peroxidase and NAD(P)H cytochrome c reductase were quantitated in polymorphonuclear leukocytes (PMN) and alveolar macrophages (AM) obtained from guinea pigs exposed up to 90 h to 85% oxygen. PMN and AM were sonicated and separated into a 16,000-g pellet, a 100,000-g pellet, and a 100,00-g supernate. Superoxide dismutase activity increased in both cells within 18 h, persisted for 66 h and decreased by 90 h. The highest rate of increase was in the 100,000-g pellet containing 3.4% of total enzyme activity in PMN but 28% in AM. The enzyme induction in PMN and AM was partially inhibited by daily intracardiac injections of 50 mg/kg actinomycin D. During oxygen exposure, catalase activity in PMN and AM decreased to 60% of its original activity, and gluthathione peroxidase was reduced in PMN to 60% and in AM to 20% of control values. Although NAD(P)H cytochrome c reductase decreased to 50% in PMN, no change was noted in AM. Upon exposure to superoxide anion, purified catalase, the glutathione peroxidase of the 100,000-g supernate, NADH, and NADPH cytochrome c reductases of the 16,000-g pellet decreased to 66+/-5%, 72+/-4%, 52+/-8%, and 40+/-9%, respectively, of their original activity. This inactivation was prevented by 0.1 mg superoxide dismutase. These in vitro observations could explain the decreased catalase and glutathione peroxidase activity demonstrated in vivo that may lead to an intracellular accumulation of hydrogen peroxide. Increased hydrogen peroxide concentrations have been found to inactivate superoxide dismutase thus impairing the first defense mechanism against superoxide anion.
Genome-wide association study identifies three new susceptibility loci for esophageal squamous-cell carcinoma in Chinese populations
Authors: Chen Wu, Zhibin Hu, Zhonghu He, Weihua Jia, Feng Wang, Yifeng Zhou, Zhihua Liu, Qimin Zhan, Yu Liu, Dianke Yu, Kan Zhai, Jiang Chang, Yan Qiao, Guangfu Jin, Zhe Liu, Yuanyuan Shen, Chuanhai Guo, Jianhua Fu, Xiaoping Miao, Wen Tan, Hongbing Shen, Yang Ke, Yixin Zeng, Tangchun Wu, Dongxin Lin
Journal: Nature Genetics (2011)
First- and second-generation immunometric PTH assays during treatment of hyperparathyroidism with cinacalcet HCl
Authors: Kevin J. Martin, Harald Juppner, Donald J. Sherrard, William G. Goodman, Mark R. Kaplan, George Nassar, Patricia Campbell, Mario Curzi, Chaim C. Harytan, Laura C. Mccary, Matthew D. Guo, Stewart A. Turner, David A. Bushinsky
Journal: Kidney International (2005)