tbuckley/cabot-search huggingface dataset:
The Accident at Chernobyl and the Medical Response
Authors: H. Jack Geiger
Journal: JAMA (1986)

THE EXPLOSION and fire at the Chernobyl number 4 nuclear power plant on April 26, 1986, was the most significant nuclear event—in terms of acute injuries and deaths, the amount of radioactivity released into the environment, the size of the affected area, and the probable magnitude of long-term consequences—since the bombings of Hiroshima and Nagasaki. It was the worst commercial nuclear power plant disaster in history, and the second to involve a meltdown of nuclear fuel—seven years after the first such instance at Three Mile Island in 1979. As in the case of previous nuclear disasters, it will be decades before the sequence of events and the consequences are fully understood. I was in the Soviet Union in early June 1986, leading a medical lecture tour under an exchange program sponsored by Physicians for Social Responsibility. This provided an opportunity for extensive discussions with the Soviet physicians in charge of
Development and Validation of a Clinical Prediction Rule for Severe Community-acquired Pneumonia
Authors: Pedro P. España, Alberto Capelastegui, Inmaculada Gorordo, Cristobal Esteban, Mikel Oribe, Miguel Ortega, Amaia Bilbao, José M. Quintana
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

Objective strategies are needed to improve the diagnosis of severe community-acquired pneumonia in the emergency department setting.To develop and validate a clinical prediction rule for identifying patients with severe community-acquired pneumonia, comparing it with other prognostic rules.Data collected from clinical information and physical examination of 1,057 patients visiting the emergency department of a hospital were used to derive a clinical prediction rule, which was then validated in two different populations: 719 patients from the same center and 1,121 patients from four other hospitals.In the multivariate analyses, eight independent predictive factors were correlated with severe community-acquired pneumonia: arterial pH < 7.30, systolic blood pressure < 90 mm Hg, respiratory rate > 30 breaths/min, altered mental status, blood urea nitrogen > 30 mg/dl, oxygen arterial pressure < 54 mm Hg or ratio of arterial oxygen tension to fraction of inspired oxygen < 250 mm Hg, age > or = 80 yr, and multilobar/bilateral lung affectation. From the beta parameter obtained in the multivariate model, a score was assigned to each predictive variable. The model shows an area under the curve of 0.92. This rule proved better at identifying patients evolving toward severe community-acquired pneumonia than either the modified American Thoracic Society rule, the British Thoracic Society's CURB-65, or the Pneumonia Severity Index.A simple score using clinical data available at the time of the emergency department visit provides a practical diagnostic decision aid, and predicts the development of severe community-acquired pneumonia.
Hebbian Learning is about contingency, not contiguity, and explains the emergence of predictive mirror neurons
Authors: Christian Keysers, David I. Perrett, Valeria Gazzola
Journal: Behavioral and Brain Sciences (2014)

Abstract Hebbian Learning should not be reduced to contiguity, as it detects contingency and causality. Hebbian Learning accounts of mirror neurons make predictions that differ from associative learning: Through Hebbian Learning, mirror neurons become dynamic networks that calculate predictions and prediction errors and relate to ideomotor theories. The social force of imitation is important for mirror neuron emergence and suggests canalization.
Gillick or Fraser? A plea for consistency over competence in children
Authors: Robert Wheeler
Journal: BMJ (2006)

Gillick and Fraser are not interchangeable 

I n most countries the issue of deciding on the ability of children to make decisions about their own medical treatment causes some dilemmas. In Britain people describe the assessment of competence of children in terms of either Gillick competence or the Fraser guidelines, as if they were interchangeable. However, they are not, and their difference needs to be made clear.

The proponents of each concept have failed to explain the differences between them and are encouraging synonymy where none exists. Research ethics committees are insisting upon the use of “Fraser,” motivated by the honourable, but false, belief that the term “Gillick competence” is unwelcome to the woman after whom it is named. National organisations are perpetuating this myth. And teachers of medical law are encountering genuine difficulty in trying to resolve this issue.

In UK law a person's 18th birthday draws the line between childhood …
The insulin A-chain epitope recognized by human T cells is posttranslationally modified
Authors: Stuart I. Mannering, Leonard C. Harrison, Nicholas A. Williamson, Jessica S. Morris, Daniel J. Thearle, Kent P. Jensen, Thomas W.H. Kay, Jamie Rossjohn, Ben A. Falk, Gerald T. Nepom, Anthony W. Purcell
Journal: The Journal of Experimental Medicine (2005)

The autoimmune process that destroys the insulin-producing pancreatic beta cells in type 1 diabetes (T1D) is targeted at insulin and its precursor, proinsulin. T cells that recognize the proximal A-chain of human insulin were identified recently in the pancreatic lymph nodes of subjects who had T1D. To investigate the specificity of proinsulin-specific T cells in T1D, we isolated human CD4(+) T cell clones to proinsulin from the blood of a donor who had T1D. The clones recognized a naturally processed, HLA DR4-restricted epitope within the first 13 amino acids of the A-chain (A1-13) of human insulin. T cell recognition was dependent on the formation of a vicinal disulfide bond between adjacent cysteine residues at A6 and A7, which did not alter binding of the peptide to HLA DR4. CD4(+) T cell clones that recognized this epitope were isolated from an HLA DR4(+) child with autoantibodies to insulin, and therefore, at risk for T1D, but not from two healthy HLA DR4(+) donors. We define for the first time a novel posttranslational modification that is required for T cell recognition of the insulin A-chain in T1D.
Lack of efficacy of rituximab in Felty's syndrome
Authors: C Sordet
Journal: Annals of the Rheumatic Diseases (2005)

<h3>Abstract</h3> In terrestrial animals, lacrimal drainage apparatus evolved to serve as conduits for tear flow. Little is known about the ontogenesis of this system. Here, we investigated tear duct origin, developmental course, genetic and cellular determinants in mouse. We report that primordial tear duct (PTD) originates from junction epithelium of the joining maxillary and lateral nasal processes, which reshapes into future tear duct branches. We identified Prickle 1 as a hallmark for tear duct outgrowth, ablation of which stalled duct elongation. In particular, the disruption of basement membrane (BM) with cytoplasmic accumulation of laminin suggests aberrant protein trafficking. Mutant embryoid bodies (EBs) derived from iPSCs recapitulate BM phenotype of the PTD exhibiting defective visceral endoderm (VE), which normally expresses high level of Prickle 1. Furthermore, replenishing mutant VE with Prickle 1 completely rescued BM but not cell polarity. Taken together, our results reveal a distinct role of Prickle 1 in regulating polarized BM secretion and deposition in precedently uncharacterized tear drainage system and VE, which is independent of apicobasal polarity establishment.
Mechanisms of sympathoadrenal failure and hypoglycemia in diabetes
Authors: P. E. Cryer
Journal: Journal of Clinical Investigation (2006)

A reduced sympathoadrenal response, induced by recent antecedent hypoglycemia, is the key feature of hypoglycemia-associated autonomic failure (HAAF) and, thus, the pathogenesis of iatrogenic hypoglycemia in diabetes. Understanding of the mechanism(s) of that reduced response awaits new insight into its basic molecular, cellular, organ, and whole-body physiology and pathophysiology in experimental models. In this issue of the JCI, McCrimmon and colleagues report that application of urocortin I (a corticotrophin-releasing factor receptor-2 agonist) to the ventromedial hypothalamus reduces the glucose counterregulatory response to hypoglycemia in rats (see the related article beginning on page 1723). Thus, hypothalamic urocortin I release during antecedent hypoglycemia is, among other possibilities, a potential mechanism of HAAF.
Carbonic Anhydrase IX Promotes Myeloid-Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production
Authors: Shawn C. Chafe, Yuanmei Lou, Jaclyn Sceneay, Marylou Vallejo, Melisa J. Hamilton, Paul C. McDonald, Kevin L. Bennewith, Andreas Möller, Shoukat Dedhar
Journal: Cancer Research (2015)

Abstract The mobilization of bone marrow–derived cells (BMDC) to distant tissues before the arrival of disseminated tumor cells has been shown preclinically to facilitate metastasis through the establishment of metastatic niches. Primary tumor hypoxia has been demonstrated to play a pivotal role in the production of chemokines and cytokines responsible for the mobilization of these BMDCs, especially in breast cancer. Carbonic anhydrase IX (CAIX, CA9) expression is highly upregulated in hypoxic breast cancer cells through the action of hypoxia-inducible factor-1 (HIF1). Preclinical evidence has demonstrated that CAIX is required for breast tumor growth and metastasis; however, the mechanism by which CAIX exerts its prometastatic function is not well understood. Here, we show that CAIX is indispensable for the production of granulocyte colony-stimulating factor (G-CSF) by hypoxic breast cancer cells and tumors in an orthotopic model. Furthermore, we demonstrate that tumor-expressed CAIX is required for the G-CSF–driven mobilization of granulocytic myeloid-derived suppressor cells (MDSC) to the breast cancer lung metastatic niche. We also determined that CAIX expression is required for the activation of NF-κB in hypoxic breast cancer cells and constitutive activation of the NF-κB pathway in CAIX-depleted cells restored G-CSF secretion. Together, these findings identify a novel hypoxia-induced CAIX–NF-κB–G-CSF cellular signaling axis culminating in the mobilization of granulocytic MDSCs to the breast cancer lung metastatic niche. Cancer Res; 75(6); 996–1008. ©2015 AACR.
Bmi1, stem cells, and senescence regulation
Authors: In-Kyung Park, Sean J. Morrison, Michael F. Clarke
Journal: Journal of Clinical Investigation (2004)

Stem cells generate the differentiated cell types within many organs throughout the lifespan of an organism and are thus ultimately responsible for the longevity of multicellular organisms. Therefore, senescence of stem cells must be prevented. Bmi1 is required for the maintenance of adult stem cells in some tissues partly because it represses genes that induce cellular senescence and cell death.
Role of β3-adrenoceptors for intrahepatic resistance and portal hypertension in liver cirrhosis
Authors: Jonel Trebicka, Martin Hennenberg, Andrea Schulze Pröbsting, Wim Laleman, Sabine Klein, Michaela Granzow, Frederik Nevens, Johan Zaagsma, Jörg Heller, Tilman Sauerbruch
Journal: Hepatology (2009)

Increased intrahepatic resistance and splanchnic blood flow cause portal hypertension in liver cirrhosis. Nonselective beta-adrenoceptor (beta-AR) antagonists have beneficial effects on hyperdynamic circulation and are in clinical use. In this context, the role of the beta(3)-AR is undefined. Here we investigated their expression and role in portal hypertension in patients and rats with liver cirrhosis. We analyzed cirrhotic human and rat tissues (liver, splanchnic vessels) and primary rat cells. Protein expression of beta(3)-AR was determined by western blot and messenger RNA (mRNA) levels by reverse-transcription polymerase chain reaction (RT-PCR). Activities of Rho-kinase and the nitric oxide (NO) effector protein kinase G (PKG) were assessed by way of substrate phosphorylation (moesin, vasodilator-stimulated phosphoprotein [VASP]). Cyclic 3',5' adenosine monophosphate (cAMP) accumulation was determined by an enzyme-immunoassay kit. The effects of selective beta(3)-AR agonists (CGP12177A, BRL37344) and antagonist (SR59230A) were investigated by collagen matrix contraction of hepatic stellate cells (HSCs), in situ liver perfusions, and in vivo hemodynamic parameters in bile duct ligation and carbon tetrachloride intoxication in cirrhotic rats. In cirrhosis of humans and rats, beta(3)-AR expression is markedly increased in hepatic and in splanchnic tissues. Stimulation of beta(3)-AR leads to relaxation of HSCs by way of cAMP accumulation, and by inhibition of Rho-kinase activity; any role of NO and its effector PKG was not observed. beta(3)-AR agonists decrease intrahepatic resistance and portal pressure in cirrhotic rats.There is a marked hepatic and mesenteric up-regulation of beta(3)-ARs in human cirrhosis and in two different animal models of cirrhosis. The beta(3)-AR-agonists should be further evaluated for therapy of portal hypertension.
Improvement of Nonalcoholic Fatty Liver Disease With Carnitine-Orotate Complex in Type 2 Diabetes (CORONA): A Randomized Controlled Trial
Authors: Ji Cheol Bae, Won Young Lee, Kun Ho Yoon, Joong Yeol Park, Hyun Sik Son, Kyung Ah Han, Kwan Woo Lee, Jeong Taek Woo, Young Cheol Ju, Won Jae Lee, Yoon Young Cho, Moon-Kyu Lee
Journal: Diabetes Care (2015)

We aimed to evaluate the effects of carnitine-orotate complex in patients with nonalcoholic fatty liver disease (NAFLD) and diabetes.Eight hospitals in Korea participated in this randomized, controlled, double-blind trial of patients with diabetes and NAFLD. Seventy-eight patients were randomly assigned in a 1:1 ratio to receive carnitine-orotate complex (824 mg, three times daily) or matching placebo. The primary study outcome was decline in alanine aminotransferase (ALT) to the normal range. Secondary study outcomes were change in ALT, radiological hepatic steatosis, parameters for anthropometry, liver function, lipid profiles, and glycemic control. Hepatic steatosis was assessed using Hounsfield units on noncontrast computed tomography (CT) imaging with hepatic attenuation.After 12 weeks of treatment, compared with placebo group, carnitine-orotate complex-treated participants had a significantly higher rate of normalization of serum ALT level (17.9% vs. 89.7%, P < 0.001). On hepatic CT analysis, participants treated with carnitine-orotate complex showed an increased liver attenuation index (0.74 ± 8.05 vs. 6.21 ± 8.96, P < 0.008). A significant decrease in HbA1c was observed in the carnitine-orotate complex group (-0.33 ± 0.82% [-3.6 ± 9.0 mmol/mol], P = 0.007), but no significant change was seen in the placebo group.Treatment with carnitine-orotate complex improves serum ALT and may improve hepatic steatosis as assessed by CT in patients with diabetes and NAFLD. Further studies using more advanced magnetic resonance imaging and liver histology as an end point are needed to assess its efficacy in NAFLD.
Qualitative Research: Reaching the parts other methods cannot reach: an introduction to qualitative methods in health and health services research
Authors: C. Pope, N. Mays
Journal: BMJ (1995)

Qualitative research methods have a long history in the social sciences and deserve to be an essential component in health and health services research. Qualitative and quantitative approaches to research tend to be portrayed as antithetical; the aim of this series of papers is to show the value of a range of qualitative techniques and how they can complement quantitative research.
Tumor-Associated Tn-MUC1 Glycoform Is Internalized through the Macrophage Galactose-Type C-Type Lectin and Delivered to the HLA Class I and II Compartments in Dendritic Cells
Authors: Chiara Napoletano, Aurelia Rughetti, Mads P. Agervig Tarp, Julia Coleman, Eric P. Bennett, Gianfranco Picco, Patrizio Sale, Kaori Denda-Nagai, Tatsuro Irimura, Ulla Mandel, Henrik Clausen, Luigi Frati, Joyce Taylor-Papadimitriou, Joy Burchell, Marianna Nuti
Journal: Cancer Research (2007)

Abstract The type of interaction between tumor-associated antigens and specialized antigen-presenting cells such as dendritic cells (DCs) is critical for the type of immunity that will be generated. MUC1, a highly O-glycosylated mucin, is overexpressed and aberrantly glycosylated in several tumor histotypes. This results in the expression of tumor-associated glycoforms and in MUC1 carrying the tumor-specific glycan Tn (GalNAcα1-O-Ser/Thr). Glycopeptides corresponding to three tandem repeats of MUC1, enzymatically glycosylated with 9 or 15 mol of GalNAc, were shown to specifically bind and to be internalized by immature monocyte-derived DCs (iDCs). Binding required calcium and the GalNAc residue and was competed out by GalNAc polymer and Tn-MUC1 or Tn-MUC2 glycopeptides. The macrophage galactose-type C-type lectin (MGL) receptor expressed on iDCs was shown to be responsible for the binding. Confocal analysis and ELISA done on subcellular fractions of iDCs showed that the Tn-MUC1 glycopeptides colocalized with HLA class I and II compartments after internalization. Importantly, although Tn-MUC1 recombinant protein was bound and internalized by MGL, the glycoprotein entered the HLA class II compartment, but not the HLA class I pathway. These data indicate that MGL expressed on iDCs is an optimal receptor for the internalization of short GalNAcs carrying immunogens to be delivered into HLA class I and II compartments. Such glycopeptides therefore represent a new way of targeting the HLA class I and II pathways of DCs. These results have possible implications in designing cancer vaccines. [Cancer Res 2007;67(17):8358–67]
Subcellular platelet factor VIII antigen and von Willebrand factor.
Authors: R L Nachman, E A Jaffe
Journal: The Journal of Experimental Medicine (1975)

Subcellular membrane and granule fractions derived from human platelets contain factor VIIII antigen and von Willebrand factor activity but not factor VII procoagulant activity. Circulating platelets constitute a significant reservoir of plasma factor VIII antigen, containing approximately 15% of the amount of factor VIII antigen present in platelet-poor plasma. The antibiotic ristocetin, which aggregates human platelets in the presence of von Willebrand factor, nonspecifically precipitates platelet membrane factor VIII antigen. Thus normal platelets contain surface-bound as well as internally stored von Willebrand factor, a protein synthesized by endothelial cells which is necessary for normal platelet function in vivo.
Lestaurtinib (CEP701) is a JAK2 inhibitor that suppresses JAK2/STAT5 signaling and the proliferation of primary erythroid cells from patients with myeloproliferative disorders
Authors: Elizabeth O. Hexner, Cynthia Serdikoff, Mahfuza Jan, Cezary R. Swider, Candy Robinson, Shi Yang, Thelma Angeles, Stephen G. Emerson, Martin Carroll, Bruce Ruggeri, Pawel Dobrzanski
Journal: Blood (2007)
Diagnostic accuracy of magnetic resonance colonography for the evaluation of disease activity and severity in ulcerative colitis: a prospective study
Authors: Ingrid Ordás, Jordi Rimola, Orlando García-Bosch, Sonia Rodríguez, Marta Gallego, María Josefina Etchevers, María Pellisé, Faust Feu, Begoña González-Suárez, Carmen Ayuso, Elena Ricart, Julián Panés
Journal: Gut (2012)

<h3>Objective</h3> The aim of this study was to determine the diagnostic accuracy of magnetic resonance colonography (MRC) for the evaluation of disease activity and severity in patients with ulcerative colitis (UC) using endoscopy as the reference standard. <h3>Methods</h3> Fifty patients with UC underwent colonoscopy and MRC for the evaluation of disease activity. All patients were prospectively and consecutively included. Endoscopic activity was evaluated globally and on a segment basis using the modified Baron score (MBS), and also classified as absent, mild to moderate (inflammation without ulcers) or severe (presence of ulceration). MRC parameters evaluated in each segment were: wall thickness, pre- and post-contrast wall signal intensity, relative contrast enhancement (RCE), mural oedema, ulcers, enlarged lymph nodes and the comb sign. <h3>Results</h3> Independent predictors for endoscopic activity on a segment basis were RCE (p=0.006), presence of oedema (p=0.003), enlarged lymph nodes (p&lt;0.001) and the comb sign (p&lt;0.001). A segmental simplified MRC index (MRC-S) ≥1 detected endoscopic inflammation with high diagnostic accuracy (sensitivity 87%, specificity 88%, area under the curve (AUC) 0.95; p&lt;0.001). MRC-S index ≥2 detected severe lesions with high sensitivity (83%) and specificity (82%) with an AUC of 0.91 (p&lt;0.001). The MRC-S index strongly correlated with the MBS (r=0.81, p&lt;0.001) and with the subjective assessment of the radiologists for the evaluation of disease severity (r=0.77, p&lt;0.001). <h3>Conclusions</h3> MRC has a high accuracy for the diagnosis of disease activity and severity in UC.
Latex Gloves with a Lower Protein Content Reduce Bronchial Reactions in Subjects with Occupational Asthma Caused by Latex
Authors: Olivier Vandenplas, Jean-Pierre Delwiche, Suzanne Depelchin, Yves Sibille, Raymond Vande Weyer, Luc Delaunois
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Latex gloves have been documented as causing rhinitis and asthma. Using inhalation challenges, we evaluated the bronchial response to hypoallergenic gloves in eight health care workers with latex-induced asthma. The subjects were exposed to the powdered latex gloves causing asthma at work and various brands of gloves with a lower protein content, either low-powdered, nonpowdered, or powdered. Exposure to hypoallergenic gloves resulted in the absence (in six subjects) or a significant reduction (in two subjects) of bronchial response. The effects of repeated exposure to hypoallergenic gloves was assessed in two subjects who did not demonstrate changes in peak expiratory flow rates and nonspecific bronchial responsiveness to histamine. This study on a limited number of patients suggests that the use of hypoallergenic gloves could be an effective means of reducing the risk of asthmatic reactions in health care workers with latex-induced asthma when complete avoidance cannot be achieved. The long-term effect of exposure as well as the widespread use of hypoallergenic gloves warrant further investigation on larger cohorts of subjects.
Specific airway resistance is overestimated during tidal breathing vs panting in healthy children
Authors: Lauriane Coutier, Claude Bonabel, Bruno Demoulin, Than LeTuan, Iulia Ioan, Silvia Varechova, Cyril Schweitzer, François Marchal
Journal: European Respiratory Journal (2011)

Rationale:  Modern plethysmographic equipments allow the measurement of specific airway resistance (sRaw) during tidal breathing (tb), a potentially useful technique in children unable to perform the panting maneuver (p), a reference technique to minimize the thermal artifact. Equipment softwares are implemented with algorithms to correct for this artifact when computing sRawtb. It is not known how well this correction performs with reference to sRawp in children. The hypothesis tested here is that both techniques provide similar estimates of sRaw.   Objective:  To compare sRawtb and sRawp in children.   Methods:  sRawtb and sRawp were measured in 6 healthy children aged 7-10 years, using a commercially available pressure plethysmograph.   Results:  sRawtb (mean ± sd = 10.4±2.0 hPa·sec; breathing rate = 0.5±0.1 Hz) was significantly larger (p=0.006) than sRawp (5.8±2.2 hPa·sec, breathing rate = 3.1±0.5 Hz). The finding hold true for Raw computed from the associated measurement of thoracic gas volume (Rawtb = 6.3±1.2 hPa·sec/L; Rawp = 2.9±1.0 hPa·sec/L, p=0.005).   Conclusion:  sRaw is significantly overestimated by tb as compared with p. This is possibly explained by non instantaneous changes of gas temperature and humidity in the airways, a fact that may not be taken into account in the correction algorithm. The impact of overestimating sRawtb9s - and hence Rawtb - on routine airway function testing in patients has to be identified.