tbuckley/cabot-search huggingface dataset:
Pathophysiological relevance of neutrophils in acetaminophen hepatotoxicity
Authors: Hartmut Jaeschke, Mitchell R. McGill, David C. Williams
Journal: Hepatology (2012)

We read with interest the recent article by Marques et al.1 on the release of damage-associated molecular patterns during acetaminophen (APAP) hepatotoxicity in mice and humans. We were pleased to learn that the authors were able to confirm certain previously published data, especially the release of mitochondrial products in human pathophysiology, which we recently reported.2 However, we have concerns regarding the conclusion that neutrophils are aggravating APAP-induced hepatotoxicity based on the data presented.1 Pretreatment with the neutropenia-inducing antibody Gr-1 induces a preconditioning effect with up-regulation of numerous genes, many of which are highly protective against APAP hepatotoxicity.3 Thus, no reliable conclusions regarding the involvement of neutrophils can be obtained from these experiments. These data have been presented in the past and the problems have been extensively discussed.3-5 It is puzzling that the authors simply repeated the same mistakes that were previously pointed out. In contrast, treatment with Gr-1 after APAP did not affect liver injury6 and there is no evidence that neutrophils are even activated or primed during the major injury phase.5 The report that coincubation of isolated neutrophils with hepatoma cells leads to cell killing in vitro has no relevance for an alleged neutrophil-induced liver injury during APAP hepatotoxicity in vivo. These experimental conditions have nothing in common with the mechanism of APAP hepatotoxicity or neutrophil-induced killing of hepatocytes in vivo. The beneficial effect of drugs that are receptor antagonists for CXC chemokine receptor 2 and formyl-peptide receptor 1 is interesting. However, the authors have not tested if any of the drugs or the solvents affected the metabolic activation of APAP, which is critical for sound mechanistic interpretation of the data, or if they had off-target effects that could lead to protection independent of the receptor antagonism. In addition, evaluating only a single late timepoint with reduced injury and fewer neutrophils is insufficient, as the decrease in neutrophil infiltration could simply be a consequence of less liver injury. Taken together, the present study, which in part repeats previous experiments and mistakes, does not support the hypothesis that neutrophils are critical for APAP hepatotoxicity. Hartmut Jaeschke Ph.D.*, Mitchell R. McGill B.Sc.*, C. David Williams B.Sc.*, * Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS.
Don Perlis and Jonathan: The Augenblick Says Phenylketonuria
Authors: W. Foster Eich
Journal: JAMA (1993)

To the Editor.  —The cover and cover storyDon Perlis and Jonathan1present an interesting Augenblicksdiagnose (eye-blink diagnosis).  I could not have guessed that the boy was retarded. But told that he is, I am almost certain that he has phenylketonuria. The boy's complexion is much lighter than his father's, and the paleness of his eyes is especially striking. This is highly suggestive of phenylketonuria, although not pathognomonic.  The metabolic block in phenylketonuria prevents phenylalanine from being converted to tyrosine. Toxic levels of phenylalanine accumulate and cause mental retardation. The resulting low levels of tyrosine, a melanin precursor, result in decreased melanin synthesis. The affected child is typically much fairer in complexion than other members of his family, though not as pale as an albino.  Why was Jonathan not diagnosed and treated in infancy? Diet therapy is capable of greatly moderating the disease and resulting in normal or near-normal
First-in-human, Pharmacokinetic and Pharmacodynamic Phase I Study of Resminostat, an Oral Histone Deacetylase Inhibitor, in Patients with Advanced Solid Tumors
Authors: André T. Brunetto, Joo Ern Ang, Rohit Lal, David Olmos, L. Rhoda Molife, Rebecca Kristeleit, Ann Parker, Isabel Casamayor, Muyibat Olaleye, Anna Mais, Bernhard Hauns, Vera Strobel, Bernd Hentsch, Johann S. de Bono
Journal: Clinical Cancer Research (2013)

Abstract Purpose: This first-in-human dose-escalating trial investigated the safety, tolerability, maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and pharmacodynamics of the novel histone deacetylase (HDAC) inhibitor resminostat in patients with advanced solid tumors. Experimental Design: Resminostat was administered orally once-daily on days 1 to 5 every 14 days at 5 dose levels between 100 and 800 mg. Safety, pharmacokinetics, pharmacodynamics including histone acetylation and HDAC enzyme activity, and antitumor efficacy were assessed. Results: Nineteen patients (median age 58 years, range 39–70) were treated. At 800 mg, 1 patient experienced grade 3 nausea and vomiting, grade 2 liver enzyme elevation, and grade 1 hypokalemia and thrombocytopenia; these were declared as a combined DLT. No other DLT was observed. Although an MTD was not reached and patients were safely dosed up to 800 mg, 3 of 7 patients treated with 800 mg underwent dose reductions after the DLT-defining period due to cumulative gastrointestinal toxicities and fatigue. All toxicities resolved following drug cessation. No grade 4 treatment-related adverse event was observed. The pharmacokinetic profile was dose-proportional with low inter-patient variability. Pharmacodynamic inhibition of HDAC enzyme was dose-dependent and reached 100% at doses ≥400 mg. Eleven heavily pretreated patients had stable disease and 1 patient with metastatic thymoma had a 27% reduction in target lesion dimensions. Conclusions: Resminostat was safely administered with a dose-proportional pharmacokinetic profile, optimal on-target pharmacodynamic activity at dose levels ≥400 mg and signs of antitumor efficacy. The recommended phase II dose is 600 mg once-daily on days 1 to 5 every 14 days. Clin Cancer Res; 19(19); 5494–504. ©2013 AACR.
Long-Term Impact of Neonatal Breast-Feeding on Body Weight and Glucose Tolerance in Children of Diabetic Mothers
Authors: Andreas Plagemann, Thomas Harder, Kerstin Franke, Rainer Kohlhoff
Journal: Diabetes Care (2002)

Offspring born to women with pregnancies complicated by diabetes are at increased childhood risk of developing obesity and impaired glucose tolerance (IGT). In population-based studies, breast-feeding has been shown to be protective against obesity and diabetes later in life. To date, the role of breast-feeding on offspring of diabetic mothers (ODM) has not been investigated in this context.A total of 112 ODM (type 1 diabetes, n = 83; gestational diabetes, n = 29) were evaluated prospectively for impact of ingestion of either diabetic breast milk (DBM) or nondiabetic banked donor breast milk (BBM) during the early neonatal period (day 1-7 of life) on relative body weight and glucose tolerance at a mean age of 2 years.There was a positive correlation between the volume of DBM ingested and risk of overweight at 2 years of age (odds ratio [OR] 2.47, 95% CI 1.25-4.87). In contrast, the volume of BBM ingested was inversely correlated to body weight at follow-up (P = 0.001). Risk of childhood IGT decreased by increasing amounts of BBM ingested neonatally (OR 0.19, 95% CI 0.05-0.70). Stepwise regression analysis showed volume of DBM to be the only significant predictor of relative body weight at 2 years of age (P = 0.001).Early neonatal ingestion of breast milk from diabetic mothers may increase risk of becoming overweight and, consequently, developing IGT during childhood. Additional studies are needed to assess long-term consequences that might result from the type of neonatal nutrition in ODM.
The C19-mineralocorticoids in hypertension.
Authors: J A Sennett, L R Yarbro, P E Slaton, J W Hollifield, G W Liddle
Journal: Circulation Research (1977)

The excretion rates of the C19-mineralcorticoids, 16beta-hydroxy-DHEA and 16-oxo-androstenediol, were measured in subjects with low-renin essential hypertension and toxemia of pregnancy. C19-mineralocorticoid excretion in low-renin essential hypertension ranged from 70-790 microgram per day. No significant difference in 16beta-hydroxy-DHEA and 16-oxo-androstenediol excretion was found between these subjects and normal controls. Subjects with toxemia of pregnancy excreted between 350 and 2500 microgram per day of these steroids. There was no significant difference between toxemic and normal pregnancy. Thus, 16beta-hydroxy - DHEA and 16-oxo-androstenediol probably do not play an important role in either low-renin essential hypertension or toxemia of pregnancy.
Intermittent failure of local conduction during ventricular tachycardia.
Authors: J M Miller, J A Vassallo, W C Hargrove, M E Josephson
Journal: Circulation (1985)

Forty-three patients with sustained ventricular tachycardia (VT) caused by prior myocardial infarction underwent intraoperative endocardial activation mapping during a total of 122 episodes of VT. Electrograms obtained during mapping were analyzed to determine the prevalence of local conduction failure during VT (defined as a portion of the local electrogram that did not repeat with every tachycardia cycle). Local conduction failure during VT was observed in 37 (86%) patients and 73 (65%) tachycardias. VT in which local conduction failure was observed were faster than VTs without local conduction failure (cycle length 315 vs 345 msec; p less than .05). Local conduction failure occurred most frequently at or near sites having the earliest recorded electrical activity during VT ("site of origin"). Twenty-three patients also had sinus rhythm endocardial mapping at the time of surgery. Areas with abnormal or fractionated electrograms in sinus rhythm were more likely to demonstrate local conduction failure in VT than areas with normal electrograms in sinus rhythm (16% vs 8%; p less than .01). Although the mechanism responsible for local conduction failure in VT is unclear, it is a common occurrence and is significant in that it can occasionally mimic "early" sites of endocardial activation, unless enough VT cycles are observed at a given site.
Phenotypical Manifestations of Mutations in the Genes Encoding Subunits of the Cardiac Sodium Channel
Authors: Arthur A.M. Wilde, Ramon Brugada
Journal: Circulation Research (2011)

Variations in the gene encoding for the major sodium channel (Na(v)1.5) in the heart, SCN5A, has been shown to cause a number of arrhythmia syndromes (with or without structural changes in the myocardium), including the long-QT syndrome (type 3), Brugada syndrome, (progressive) cardiac conduction disease, sinus node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy. Of equal importance are variations in genes encoding for various subunits and regulatory proteins interacting with the α-subunit Na(v)1.5 and modifying its function. Based on detailed studies of genotype-phenotype relationships in these disease entities, on detailed studies of the basic electrophysiological phenotypes (heterologous expressed wild-type and mutant sodium channels and their interacting proteins), and on attempts to integrate the obtained knowledge, the past 15 years has witnessed an explosion of knowledge about these disease entities.
Glucose-induced endothelial heparanase secretion requires cortical and stress actin reorganization
Authors: Fang Wang, Ying Wang, Min Suk Kim, Prasanth Puthanveetil, Sanjoy Ghosh, Dan S. Luciani, James D. Johnson, Ashraf Abrahani, Brian Rodrigues
Journal: Cardiovascular Research (2010)

Heparanase, which specifically cleaves carbohydrate chains of heparan sulfate, has been implicated in the pathology of diabetes-associated complications. Using high glucose (HG) to replicate hyperglycaemia observed following diabetes, the present study was designed to determine the mechanism by which HG initiates endothelial heparanase secretion.To examine the effect of HG on endothelial heparanase, bovine coronary artery endothelial cells were incubated with 25 mM glucose. Strategies using different agonists and antagonists were used to determine the mechanism behind HG-induced heparanase secretion. In endothelial cells, heparanase colocalized with lysosomes predominately around the nucleus, and HG caused its dispersion towards the plasma membrane for subsequent secretion. ATP release, purinergic receptor activation, cortical actin disassembly, and stress actin formation were essential for this HG-induced heparanase secretion. With HG, phosphorylation of filamin likely contributed to the cortical actin disassembly, whereas Ca(2+)/calmodulin-dependent protein kinase II and p38 mitogen-activated protein kinase /heat shock protein 25 phosphorylation mediated stress actin formation. The endothelial secreted heparanase in response to HG demonstrated endoglucuronidase activity, cleaved heparan sulfate, and released attached proteins like lipoprotein lipase and basic fibroblast growth factor.Our results suggest that HG is a potent stimulator of endothelial heparanase secretion. These data may assist in devising new therapeutic strategies to prevent or delay the cardiovascular complications associated with diabetes.
β-Agonists and asthma: too much of a good thing?
Authors: Stephanie A. Shore, Jeffrey M. Drazen
Journal: Journal of Clinical Investigation (2003)

In an unusual paradox, asthmatics who are chronically treated with bronchodilating beta-agonists sometimes experience a worsening of their condition. A new study describes one possible mechanism and reveals a potential new therapeutic target in the treatment of asthma.
Cooperative effects of colony-stimulating factor 1 and recombinant interleukin 2 on proliferation and induction of cytotoxicity of macrophage precursors generated from mouse bone marrow cell cultures.
Authors: H Li, R Schwinzer, M Baccarini, M L Lohmann-Matthes
Journal: The Journal of Experimental Medicine (1989)

Precursor cells for NK activity, present in the light fraction of fresh mouse bone marrow, were cultivated in vitro in the presence of either CSF-1, IL-2, or a combination of both factors. In the presence of only CSF-1, strong proliferation was induced. Cells quickly passed the macrophage precursor stage and matured to typical macrophages. Neither granula formation nor NK activity were induced. Under culture conditions with only IL-2 NK activity had developed after 3 d, however, no significant proliferation occurred. In the presence of both factors strong proliferation was induced, and concomitantly, granula formation and NK activity developed. Apparently, proliferation depended on CSF-1 and granula formation, and NK cytotoxicity was induced by IL-2. When proliferating cells with strong anti-YAC-1 activity from a culture in CSF-1 plus IL-2 were further cultivated in only IL-2, the content of granula further increased, whereas proliferation gradually stopped. In contrast, when these cells from CSF-1 plus IL-2 culture were further cultivated in only CSF-1, granula disappeared and NK activity was lost, whereas sustained proliferation and differentiation to macrophages occurred. Only under culture conditions with both factors were proliferation and NK activity both maintained. More than 90% of cells from a 3-d culture in CSF-1 plus IL-2 expressed the NK 1.1. marker, whereas F4/80 was only marginally detected by FACS analysis. After two further days in culture, 70% of the cells expressed F4/80 and 60% coexpressed NK 1.1. and F4/80. By setting the size scatter in order to gate for large granular cells, a population was obtained with 100% coexpression of NK1.1. and F4/80. The data indicate that early cells of the macrophage lineage can develop into different functional and morphological directions depending on the varying influence of IL-2 and CSF-1.
Categorising sports injuries in epidemiological studies: the subsequent injury categorisation (SIC) model to address multiple, recurrent and exacerbation of injuries
Authors: Caroline F Finch, Jill Cook
Journal: British Journal of Sports Medicine (2013)

Objective Sports injuries are often recurrent and there is wide recognition that a subsequent injury (of either the same or a different type) can be strongly influenced by a previous injury. Correctly categorising subsequent injuries (multiple, recurrent, exacerbation or new) requires substantial clinical expertise, but there is also considerable value in combining this expertise with more objective statistical criteria. This paper presents a new model, the subsequent injury categorisation (SIC) model, for categorising subsequent sports injuries that takes into account the need to include both acute and overuse injuries and ten different dependency structures between injury types. Methods The suitability of the SIC model was demonstrated with date ordered sports injury data from a large injury database from community Australian football players over one playing season. A subsequent injury was defined to have occurred in the subset of players with two or more reported injuries. Results 282 players sustained 469 subsequent injuries of which 15.6% were coded to categories representing injuries that were directly related to previous index injuries. This demonstrates that players can sustain a number of injuries over one playing season. Many of these will be unrelated to previous injuries but subsequent injuries that are related to previous injury occurrences are not uncommon. Conclusion The handling of subsequent sports injuries is a substantial challenge for the sports medicine field—both in terms of injury treatment and in epidemiological research to quantify them. Application of the SIC model allows for multiple different injury types and relationships within players, as well as different index injuries.
Fumarates improve psoriasis and multiple sclerosis by inducing type II dendritic cells
Authors: Kamran Ghoreschi, Jürgen Brück, Christina Kellerer, Caishu Deng, Haiyan Peng, Oliver Rothfuss, Rehana Z. Hussain, Anne R. Gocke, Annedore Respa, Ivana Glocova, Nadejda Valtcheva, Eva Alexander, Susanne Feil, Robert Feil, Klaus Schulze-Osthoff, Rudolf A. Rupec, Amy E. Lovett-Racke, Ralf Dringen, Michael K. Racke, Martin Röcken
Journal: The Journal of Experimental Medicine (2011)

Fumarates improve multiple sclerosis (MS) and psoriasis, two diseases in which both IL-12 and IL-23 promote pathogenic T helper (Th) cell differentiation. However, both diseases show opposing responses to most established therapies. First, we show in humans that fumarate treatment induces IL-4–producing Th2 cells in vivo and generates type II dendritic cells (DCs) that produce IL-10 instead of IL-12 and IL-23. In mice, fumarates also generate type II DCs that induce IL-4–producing Th2 cells in vitro and in vivo and protect mice from experimental autoimmune encephalomyelitis. Type II DCs result from fumarate-induced glutathione (GSH) depletion, followed by increased hemoxygenase-1 (HO-1) expression and impaired STAT1 phosphorylation. Induced HO-1 is cleaved, whereupon the N-terminal fragment of HO-1 translocates into the nucleus and interacts with AP-1 and NF-κB sites of the IL-23p19 promoter. This interaction prevents IL-23p19 transcription without affecting IL-12p35, whereas STAT1 inactivation prevents IL-12p35 transcription without affecting IL-23p19. As a consequence, GSH depletion by small molecules such as fumarates induces type II DCs in mice and in humans that ameliorate inflammatory autoimmune diseases. This therapeutic approach improves Th1- and Th17-mediated autoimmune diseases such as psoriasis and MS by interfering with IL-12 and IL-23 production.
Comparative Expression Profiling in Pulmonary Fibrosis Suggests a Role of Hypoxia-inducible Factor-1α in Disease Pathogenesis
Authors: Argyris Tzouvelekis, Vaggelis Harokopos, Triantafillos Paparountas, Nikos Oikonomou, Aristotelis Chatziioannou, George Vilaras, Evangelos Tsiambas, Andreas Karameris, Demosthenes Bouros, Vassilis Aidinis
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Despite intense research efforts, the etiology and pathogenesis of idiopathic pulmonary fibrosis remain poorly understood.Objectives: To discover novel genes and/or cellular pathways involved in the pathogenesis of the disease.Methods: We performed expression profiling of disease progression in a well-characterized animal model of the disease. Differentially expressed genes that were identified were compared with all publicly available expression profiles both from human patients and animal models. The role of hypoxia-inducible factor (HIF)-1α in disease pathogenesis was examined with a series of immunostainings, both in the animal model as well as in tissue microarrays containing tissue samples of human patients, followed by computerized image analysis.Measurements and Main Results: Comparative expression profiling produced a prioritized gene list of high statistical significance, which consisted of the most likely disease modifiers identified so far in pulmonary fibrosis. Extending beyond target identification, a series of meta-analyses produced a number of biological hypotheses on disease pathogenesis. Among them, the role of HIF-1 signaling was further explored to reveal HIF-1α overexpression in the hyperplastic epithelium of fibrotic lungs, colocalized with its target genes p53 and Vegf.Conclusions: Comparative expression profiling was shown to be a highly efficient method in identifying deregulated genes and pathways. Moreover, tissue microarrays and computerized image analysis allowed for the high-throughput and unbiased assessment of histopathologic sections, adding substantial confidence in pathologic evaluations. More importantly, our results suggest an early primary role of HIF-1 in alveolar epithelial cell homeostasis and disease pathogenesis, provide insights on the pathophysiologic differences of different interstitial pneumonias, and indicate the importance of assessing the efficacy of pharmacologic inhibitors of HIF-1 activity in the treatment of pulmonary fibrosis.
Predicting Mammalian SINE Subfamily Activity from A-tail Length
Authors: G. L. Odom
Journal: Molecular Biology and Evolution (2004)

Based on previous observations that newly inserted LINEs and SINEs have particularly long 3′ A-tails, which shorten rapidly during evolutionary time, we have analyzed the rat and mouse genomes for evidence of recently inserted SINEs and LINEs. We find that the youngest predicted subfamilies of rodent identifier (ID) elements, a rodent-specific SINE derived from tRNAAla, are preferentially associated with A-tails over 50 bases in the rat genome, as predicted. Furthermore, these studies detected a subfamily of ID elements that has made over 15,000 copies that is younger than any previously reported ID subfamily. We use PCR analysis of genomic loci to demonstrate that all subfamily members tested inserted after the divergence of Rattus norvegicus from Rattus rattus. We also found evidence that the rodent B1 family of elements is much more active currently in mouse than in rat. These data provide useful estimates of recent activity from all of the mammalian retrotransposons, as well as allowing identification of the most recent insertions for use as population and speciation markers in those species. Both the current rat ID and mouse B1 elements that are active have small, specific interruptions in their 3′ A-tail sequences. We suggest that these interruptions stabilize the length of the A-tails and contribute to the activity of these subfamilies. We present a model in which the dynamics of the 3′ A-tail may be a central controlling factor in SINE activity.