tbuckley/cabot-search huggingface dataset:
Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl.
Authors: S J Martin, C P Reutelingsperger, A J McGahon, J A Rader, R C van Schie, D M LaFace, D R Green
Journal: The Journal of Experimental Medicine (1995)

A critical event during programmed cell death (PCD) appears to be the acquisition of plasma membrane (PM) changes that allows phagocytes to recognize and engulf these cells before they rupture. The majority of PCD seen in higher organisms exhibits strikingly similar morphological features, and this form of PCD has been termed apoptosis. The nature of the PM changes that occur on apoptotic cells remains poorly defined. In this study, we have used a phosphatidylserine (PS)-binding protein (annexin V) as a specific probe to detect redistribution of this phospholipid, which is normally confined to the inner PM leaflet, during apoptosis. Here we show that PS externalization is an early and widespread event during apoptosis of a variety of murine and human cell types, regardless of the initiating stimulus, and precedes several other events normally associated with this mode of cell death. We also report that, under conditions in which the morphological features of apoptosis were prevented (macromolecular synthesis inhibition, overexpression of Bcl-2 or Abl), the appearance of PS on the external leaflet of the PM was similarly prevented. These data are compatible with the notion that activation of an inside-outside PS translocase is an early and widespread event during apoptosis.
Are joints affected by gout also affected by osteoarthritis?
Authors: E. Roddy, W. Zhang, M. Doherty
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> To determine whether joints affected by gout are also affected by osteoarthritis (OA). <h3>Methods:</h3> A postal questionnaire was sent to all adults aged over 30 years registered with two general practices. The questionnaire assessed a history of gout (doctor diagnosed, or episodes suggestive of acute crystal synovitis) and medication use. Patients who possibly had gout attended for clinical assessment to verify the diagnosis on clinical grounds and assess the distribution of joints affected by acute attacks of gout and OA. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were calculated between the history of an acute attack of gout and the presence of OA at an individual joint adjusted for age, gender, body mass index and prior diuretic use in a binary logistic regression model. <h3>Results:</h3> A total of 4249 completed questionnaires were returned (32%). From 359 attendees, 164 cases of gout were clinically confirmed. A highly significant association existed between the site of acute attacks of gout and the presence of OA (aOR 7.94; 95% CI 6.27, 10.05). Analysis at individual joint sites revealed a significant association at the first metatarsophalangeal joint (aOR 2.06; 95% CI 1.28, 3.30), mid-foot (aOR 2.85; 95% CI 1.34, 6.03), knee (aOR 3.07; 95% CI 1.05, 8.96) and distal interphalangeal joints (aOR 12.67; 95% CI 1.46, 109.91). <h3>Conclusion:</h3> Acute attacks of gout at individual joint sites are associated with the presence of clinically assessed OA at that joint suggesting that OA may predispose to the localised deposition of monosodium urate crystals.
Immunomodulation: a new approach to the therapy of cirrhosis?
Authors: F. Marra, F. Annunziato
Journal: Gut (2010)

Liver cirrhosis is a leading cause of mortality in Western countries and the major risk factor for the development of hepatocellular carcinoma, a difficult to treat malignancy with a poor prognosis. In recent years, the management of cirrhotic patients has considerably improved due to better ability to deal with complications such as portal hypertensive bleeding, hepatorenal syndrome and hepatocellular carcinoma. Unless the causal agent is removed, no therapies are currently available to slow down the progressive worsening of hepatic function after the development of cirrhosis, and liver transplantation remains the only approach that has an impact in the long term. Considerable advancements have also been made in the understanding of the pathophysiology of hepatic fibrosis, and the pivotal role played by hepatic inflammation has been clearly defined. Inflammation is part of the tissue ‘wound healing’ response, and leucocyte populations differentially modulate the process of fibrogenesis, that leads to the development of cirrhosis.1 Monocytes and activated macrophages contribute to the development and progression of fibrosis via expression of numerous cytokines, such as platelet-derived growth factor and transforming growth factor-β1, or generation of reactive oxygen intermediates. The role of T cells is more complex, and the available data indicate that a Th1-polarised response is associated with reduced deposition of extracellular matrix, partly mediated by secretion of interferon (IFN)-γ, whereas Th2-related cytokines such as interleukin (IL)-4 and IL-13 cause a more rapid progression of fibrosis.1 Once cirrhosis has been established, the presence of inflammation and the related hyperproduction of cytokines, including tumour necrosis factor (TNF)-α, in the splanchnic district and in the systemic circulation, is responsible for the worsening of portal hypertension and appearance of hyperdynamic circulation.2 …
Differential Protein Stability and ALK Inhibitor Sensitivity of EML4-ALK Fusion Variants
Authors: Johannes M. Heuckmann, Hyatt Balke-Want, Florian Malchers, Martin Peifer, Martin L. Sos, Mirjam Koker, Lydia Meder, Christine M. Lovly, Lukas C. Heukamp, William Pao, Ralf Küppers, Roman K. Thomas
Journal: Clinical Cancer Research (2012)

ALK rearrangement-positive lung cancers can be effectively treated with ALK inhibitors. However, the magnitude and duration of response is heterogeneous. In addition, acquired resistance limits the efficacy of ALK inhibitors, with most upfront resistance mechanisms being unknown.By making use of the Ba/F3 cell line model, we analyzed the cytotoxic efficacy of ALK kinase inhibitors as a function of different EML4-ALK fusion variants v1, v2, v3a, and v3b as well as of three artificially designed EML4-ALK deletion constructs and the ALK fusion genes KIF5b-ALK and NPM1-ALK. In addition, the intracellular localization, the sensitivity to HSP90 inhibition and the protein stability of ALK fusion proteins were studied.Different ALK fusion genes and EML4-ALK variants exhibited differential sensitivity to the structurally diverse ALK kinase inhibitors crizotinib and TAE684. In addition, differential sensitivity correlated with differences in protein stability in EML4-ALK-expressing cells. Furthermore, the sensitivity to HSP90 inhibition also varied depending on the ALK fusion partner but differed from ALK inhibitor sensitivity patterns. Finally, combining inhibitors of ALK and HSP90 resulted in synergistic cytotoxicity.Our results might explain some of the heterogeneous responses of ALK-positive tumors to ALK kinase inhibition observed in the clinic. Thus, targeted therapy of ALK-positive lung cancer should take into account the precise ALK genotype. Furthermore, combining ALK and HSP90 inhibitors might enhance tumor shrinkage in EML4-ALK-driven tumors.
A Multicentre Study of Shigella Diarrhoea in Six Asian Countries: Disease Burden, Clinical Manifestations, and Microbiology
Authors: Lorenz von Seidlein, Deok Ryun Kim, Mohammad Ali, Hyejon Lee, XuanYi Wang, Vu Dinh Thiem, Do Gia Canh, Wanpen Chaicumpa, Magdarina D Agtini, Anowar Hossain, Zulfiqar A Bhutta, Carl Mason, Ornthipa Sethabutr, Kaisar Talukder, G. B Nair, Jacqueline L Deen, Karen Kotloff, John Clemens
Journal: PLoS Medicine (2006)

Background The burden of shigellosis is greatest in resource-poor countries. Although this diarrheal disease has been thought to cause considerable morbidity and mortality in excess of 1,000,000 deaths globally per year, little recent data are available to guide intervention strategies in Asia. We conducted a prospective, population-based study in six Asian countries to gain a better understanding of the current disease burden, clinical manifestations, and microbiology of shigellosis in Asia. Methods and Findings Over 600,000 persons of all ages residing in Bangladesh, China, Pakistan, Indonesia, Vietnam, and Thailand were included in the surveillance. Shigella was isolated from 2,927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004. The overall incidence of treated shigellosis was 2.1 episodes per 1,000 residents per year in all ages and 13.2/1,000/y in children under 60 months old. Shigellosis incidence increased after age 40 years. S. flexneri was the most frequently isolated Shigella species (1,976/2,927 [68%]) in all sites except in Thailand, where S. sonnei was most frequently detected (124/146 [85%]). S. flexneri serotypes were highly heterogeneous in their distribution from site to site, and even from year to year. PCR detected ipaH, the gene encoding invasion plasmid antigen H in 33% of a sample of culture-negative stool specimens. The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305 [6%]), Pakistan (8/242 [3%]), and Vietnam (5/282 [2%]). Conclusions Shigella appears to be more ubiquitous in Asian impoverished populations than previously thought, and antibiotic-resistant strains of different species and serotypes have emerged. Focusing on prevention of shigellosis could exert an immediate benefit first by substantially reducing the overall diarrhoea burden in the region and second by preventing the spread of panresistant Shigella strains. The heterogeneous distribution of Shigella species and serotypes suggest that multivalent or cross-protective Shigella vaccines will be needed to prevent shigellosis in Asia.
Dangers of Sulphonamides in Ear Infections
Authors: A. R. Dingley
Journal: BMJ (1944)

747of this sometimes necessary proceeding.The almost routine institution of continuous post-operative gastric suction un- doubtedly time and again saved lives by averting the ileus which so commonly occurs whether bowel be injured or not.It matters little how many layers of stitches are inserteJ to close a bowel aperture if distension is allowed to occur; one layer of Lembert stitching suffices if the bowel wall be kept lax.The restoration of lost fluid by intravenous administration in sufficient quantity kept pace with the withdrawal.There was early realization that abdominal patients have to be worked for and fought for, and that even in some of the most apparently unfavourable cases a good result can be got with such care.By the excellence of the transfusion services and by the greater exploitation of forward teams probably many more desperate cases reached an operating table than did in the last war.These two factors will invalidate any real statistical comparison.These desperate cases included not only patients with abdominal wounds but also those with both abdominal and other severe injuries such as compound fractures of the long bones.The combination is not uncommon, and is fraught with more than fourfold risks.With the above practices thoroughly carried out, with routine four-hourly post-operative morphine, and with the retention of the patient for ten days where he was operated upon, it is likely that the end-results did not at least fall lower, despite the more desperate cases, than in past wars.In order to make this paper comprehensive and yet bring it within the limits of an article I have had to omit much.Particularly do I regret omitting the names of individuals.To have mentioned some and not all would have been contrary to the spirit of the Eighth Army, in which brotherhood, kindliness, and helpfulness abounded.Acknowledgments to my seniors I make with gratitude.To Major-General W. H. Ogilvie and Brigadier J. Weddell, the chief consulting surgeons of M.E.F. and A.F.H.Q.respectively, I owe much for opportunity, advice, and
Tramadol Use and the Risk of Hospitalization for Hypoglycemia in Patients With Noncancer Pain
Authors: Jean-Pascal Fournier, Laurent Azoulay, Hui Yin, Jean-Louis Montastruc, Samy Suissa
Journal: JAMA Internal Medicine (2014)

Tramadol is a weak opioid analgesic whose use has increased rapidly, and it has been associated with adverse events of hypoglycemia.To assess whether tramadol use, when compared with codeine use, is associated with an increased risk of hospitalization for hypoglycemia.A nested case-control analysis was conducted within the United Kingdom Clinical Practice Research Datalink linked to the Hospital Episodes Statistics database of all patients newly treated with tramadol or codeine for noncancer pain between 1998 and 2012. Cohort and case-crossover analyses were also conducted to assess consistency of the results.Cases of hospitalization for hypoglycemia were matched with up to 10 controls on age, sex, and duration of follow-up. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated comparing use of tramadol with codeine. A cohort analysis, with high-dimensional propensity score-adjusted hazard ratios (HRs) and 95% CIs, was performed comparing tramadol with codeine in the first 30 days after treatment initiation. Finally, a case-crossover analysis was also performed, in which exposure to tramadol in a 30-day risk period immediately before the hospitalization for hypoglycemia was compared with 11 consecutive 30-day control periods. Odds ratios and 95% CIs were estimated using conditional logistic regression analysis.The cohort included 334,034 patients, of whom 1105 were hospitalized for hypoglycemia during follow-up (incidence, 0.7 per 1000 per year) and matched to 11,019 controls. Compared with codeine, tramadol use was associated with an increased risk of hospitalization for hypoglycemia (OR, 1.52 [95% CI, 1.09-2.10]), particularly elevated in the first 30 days of use (OR, 2.61 [95% CI, 1.61-4.23]). This 30-day increased risk was confirmed in the cohort (HR, 3.60 [95% CI, 1.56-8.34]) and case-crossover analyses (OR, 3.80 [95% CI, 2.64-5.47]).The initiation of tramadol therapy is associated with an increased risk of hypoglycemia requiring hospitalization. Additional studies are needed to confirm this rare but potentially fatal adverse event.
Antimony and health
Authors: F. A De Wolff
Journal: BMJ (1995)

monitoring of a single patient.Others have used changes in thoracic electrical impedance to measure pump performance non-invasively, but this has not given consistent results.Our current methods of predicting perioperative cardiac risk are, then, characterised by uncertainty.Surgeons should take more responsibility for defining the risk in their own population of patients; if it is sufficiently high they should adopt a protocol for assessing individual patients.This will require selection for thallium scanning on the basis of clinical risk factors, with the possibility of coronary angiography for those found to have reversible defects on thallium imaging.Further studies are urgently needed to provide a reliable algorithm for non-invasive assessment of operative risk.
Response to letter by Aramugakani<i>et al</i>
Authors: Gianfranco Ferraccioli, Frédéric A Houssiau
Journal: Annals of the Rheumatic Diseases (2014)

Understanding the interaction of local anesthetics (LAs) with plasma proteins is essential to understanding their systemic pharmacology and toxicology. The molecular determinants of LA binding to the major variant (<i>F1*S</i>) of human α<sub>1</sub>-acid glycoprotein (AGP) were therefore investigated spectrofluorometrically using whole AGP and a novel, <i>F1*S</i> variant-selective probe previously developed in our laboratory. Equilibrium- competitive displacement of this probe by LAs, observed by the recovery of AGP9s fluorescence as the quenching probe was displaced from its high-affinity site, was characterized by inhibitory dissociation constants for the various LAs. The importance of electrostatic factors was assessed by examining the pH dependent binding of an ionizable LA, lidocaine, using the quaternary lidocaine derivative QX-314 [<i>N-</i>(2,6-dimethylphenylcarbamoylmethyl) triethylammonium chloride] to control for pH dependent ionization of AGP. Uncharged lidocaine bound with at least 8 times the affinity of protonated lidocaine (<i>K<sub>D</sub></i> = 4.0 ± 0.6 μM and &gt;32 μM, respectively). This result is inconsistent with the current model of the AGP-binding site, which depicts a buried pocket having a negatively charged region that interacts with the amino termini of basic drugs. Consistent with the model, however, two sets of structurally homologous LAs (mepivacaine, ropivacaine, bupivacaine, and lidocaine, RAD-240, RAD-241, RAD-242, L-30, W-6603) demonstrated a strong positive correlation between hydrophobicity (measured as the octanol:buffer partition coefficient of the neutral species) and their free energies of dissociation. Given that the tertiary structure of AGP has proven refractory to resolution, these structure-activity studies should contribute to understanding the nature of the binding site on this important protein.
Transplantation of Blood-Derived Progenitor Cells After Recanalization of Chronic Coronary Artery Occlusion
Authors: Sandra Erbs, Axel Linke, Volker Adams, Karsten Lenk, Holger Thiele, Klaus-Werner Diederich, Frank Emmrich, Regine Kluge, Kai Kendziorra, Osama Sabri, Gerhard Schuler, Rainer Hambrecht
Journal: Circulation Research (2005)

Transplantation of blood-derived circulating progenitor cells (CPC) has been shown to improve myocardial regeneration after myocardial infarction. It remains unclear whether CPC transplantation exerts beneficial effects also in patients with chronic myocardial ischemia. We initiated a randomized, double-blind, placebo-controlled study evaluating the impact of intracoronary infusion of CPCs on coronary vasomotion and left ventricular (LV) function in patients after recanalization of chronic coronary total occlusion (CTO). After recanalization of CTO, 26 patients (age, 63±2 years; LV ejection fraction, 53±2%) were randomly assigned to the treatment (intracoronary transplantation of CPCs) or control group. Coronary flow reserve in response to adenosine (2.4 mg/min) was measured in the target vessel at the beginning of the study and after 3 months. LV function and infarct size were assessed by MRI and metabolism by 18 F deoxyglucose positron emission tomography. CPC application resulted in an increase in coronary flow reserve by 43% from 2.3±0.3 to 3.3±0.5 ( P &lt;0.05 versus beginning and control). At 3 months, the number of hibernating segments in the target region (from 2.9±0.6 to 2.0±0.6 segments, P &lt;0.05 versus beginning and control) had declined in the treatment group, whereas no significant changes were observed in the control group. MRI revealed a reduction in infarct size by 16% and an increase in LV ejection fraction by 14% in the treatment group (from 51.7±3.7 to 58.9±3.2%; P &lt;0.05 versus beginning and control) because of an augmented wall motion in the target region. Hence, intracoronary transplantation of CPCs after recanalization of CTO results in an improvement of macro- and microvascular function and contributes to the recruitment of hibernating myocardium.
Quartet-Net: A Quartet-Based Method to Reconstruct Phylogenetic Networks
Authors: Jialiang Yang, Stefan Grünewald, Xiu-Feng Wan
Journal: Molecular Biology and Evolution (2013)

Phylogenetic networks can model reticulate evolutionary events such as hybridization, recombination, and horizontal gene transfer. However, reconstructing such networks is not trivial. Popular character-based methods are computationally inefficient, whereas distance-based methods cannot guarantee reconstruction accuracy because pairwise genetic distances only reflect partial information about a reticulate phylogeny. To balance accuracy and computational efficiency, here we introduce a quartet-based method to construct a phylogenetic network from a multiple sequence alignment. Unlike distances that only reflect the relationship between a pair of taxa, quartets contain information on the relationships among four taxa; these quartets provide adequate capacity to infer a more accurate phylogenetic network. In applications to simulated and biological data sets, we demonstrate that this novel method is robust and effective in reconstructing reticulate evolutionary events and it has the potential to infer more accurate phylogenetic distances than other conventional phylogenetic network construction methods such as Neighbor-Joining, Neighbor-Net, and Split Decomposition. This method can be used in constructing phylogenetic networks from simple evolutionary events involving a few reticulate events to complex evolutionary histories involving a large number of reticulate events. A software called "Quartet-Net" is implemented and available at http://sysbio.cvm.msstate.edu/QuartetNet/.
Broadly-specific Cytotoxic T Cells Targeting Multiple HIV Antigens Are Expanded From HIV+ Patients: Implications for Immunotherapy
Authors: Sharon Lam, Julia Sung, Conrad Cruz, Paul Castillo-Caro, Minhtran Ngo, Carolina Garrido, Joann Kuruc, Nancie Archin, Cliona Rooney, David Margolis, Catherine Bollard
Journal: Molecular Therapy (2014)

Antiretroviral therapy (ART) is unable to eradicate human immunodeficiency virus type 1 (HIV-1) infection. Therefore, there is an urgent need to develop novel therapies for this disease to augment anti-HIV immunity. T cell therapy is appealing in this regard as T cells have the ability to proliferate, migrate, and their antigen specificity reduces the possibility of off-target effects. However, past human studies in HIV-1 infection that administered T cells with limited specificity failed to provide ART-independent, long-term viral control. In this study, we sought to expand functional, broadly-specific cytotoxic T cells (HXTCs) from HIV-infected patients on suppressive ART as a first step toward developing cellular therapies for implementation in future HIV eradication protocols. Blood samples from seven HIV+ patients on suppressive ART were used to derive HXTCs. Multiantigen specificity was achieved by coculturing T cells with antigen-presenting cells pulsed with peptides representing Gag, Pol, and Nef. All but two lines were multispecific for all three antigens. HXTCs demonstrated efficacy as shown by release of proinflammatory cytokines, specific lysis of antigen-pulsed targets, and the ability to suppress HIV replication in vitro. In conclusion, we are able to generate broadly-specific cytotoxic T cell lines that simultaneously target multiple HIV antigens and show robust antiviral function. Antiretroviral therapy (ART) is unable to eradicate human immunodeficiency virus type 1 (HIV-1) infection. Therefore, there is an urgent need to develop novel therapies for this disease to augment anti-HIV immunity. T cell therapy is appealing in this regard as T cells have the ability to proliferate, migrate, and their antigen specificity reduces the possibility of off-target effects. However, past human studies in HIV-1 infection that administered T cells with limited specificity failed to provide ART-independent, long-term viral control. In this study, we sought to expand functional, broadly-specific cytotoxic T cells (HXTCs) from HIV-infected patients on suppressive ART as a first step toward developing cellular therapies for implementation in future HIV eradication protocols. Blood samples from seven HIV+ patients on suppressive ART were used to derive HXTCs. Multiantigen specificity was achieved by coculturing T cells with antigen-presenting cells pulsed with peptides representing Gag, Pol, and Nef. All but two lines were multispecific for all three antigens. HXTCs demonstrated efficacy as shown by release of proinflammatory cytokines, specific lysis of antigen-pulsed targets, and the ability to suppress HIV replication in vitro. In conclusion, we are able to generate broadly-specific cytotoxic T cell lines that simultaneously target multiple HIV antigens and show robust antiviral function.