tbuckley/cabot-search huggingface dataset:
Alterations of lung and chest wall mechanics in patients with acute lung injury: effects of positive end-expiratory pressure.
Authors: P Pelosi, M Cereda, G Foti, M Giacomini, A Pesenti
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

In 16 mechanically ventilated patients with acute lung injury (ALI) (eight patients with moderate ALI [moderate group], eight patients with severe ALI [adult respiratory distress syndrome, ARDS group]) and in eight normal anesthetized-paralyzed subjects (control group), we partitioned the total respiratory system mechanics into the lung (L) and chest wall (w) mechanics using the esophageal balloon technique together with the airway occlusion technique during constant flow inflation. We measured lung elastance (Est,L), chest wall elastance (Est,w), and total lung (Rmax, L) and chest wall (Rmax,w) resistance. Rmax,L includes airway (Rmin,L) and "additional" lung resistance (DR,L). DR,L represents the "additional" component due to the viscoelastic phenomena of the lung tissues and time-constant inequalities (pendelluft). Measurements were repeated at 0, 5, and 10 cm H2O of positive end-expiratory pressure (PEEP) in the control group and at 0, 5, 10, and 15 cm H2O PEEP in patients with ALI. The end-expiratory lung volume (EELV) was measured at each level of PEEP. Specific total lung (sRmax,L), airway (sRmin,L), and "additional" lung (sDR,L) resistances were obtained as Rmax,L x EELV, Rmin,L x EELV, and DR,L x EELV, respectively. At PEEP 0 cm H2O, we found that both Est,L (23.7 +/- 5.5 and 13.8 +/- 3.3 versus 9.3 +/- 1.7 cm H2O/L; p < 0.01) and Est,w (13.2 +/- 5.4 and 9.9 +/- 2.1 versus 5.6 +/- 2.3 cm H2O/L; p < 0.01) were markedly increased in patients with ARDS and moderate ALI compared with control subjects, with a significant (p < 0.01) effect of the severity of the disease on Est,L (p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Antidepressants in pregnancy are linked to ADHD but not to autism, says study
Authors: A. O'Dowd
Journal: BMJ (2014)

Women who take antidepressants while pregnant may be raising the risk of their child developing attention deficit hyperactivity disorder (ADHD) but not autism, a study published in the journal Molecular Psychiatry has found.1

The US researchers, however, warned that any potential “modest” risk from taking antidepressants should be weighed against the possible consequences of not treating maternal depression or anxiety in each individual patient.

An apparently rapid increase in prevalence of autism spectrum disorder (ASD) over the past decade has increased efforts to identify potentially modifiable risks, although experts believe that much of the liability for autism is inherited and that environmental factors, not yet clearly identified, might add to the risk.

Previous studies2 3 4 have had contradictory findings about whether prenatal exposure to serotonergic drugs …
Molecular Pathways: Gene–Environment Interactions Regulating Dietary Fiber Induction of Proliferation and Apoptosis via Butyrate for Cancer Prevention
Authors: Scott J. Bultman
Journal: Clinical Cancer Research (2013)

Abstract Gene–environment interactions are so numerous and biologically complicated that it can be challenging to understand their role in cancer. However, dietary fiber and colorectal cancer prevention may represent a tractable model system. Fiber is fermented by colonic bacteria into short-chain fatty acids such as butyrate. One molecular pathway that has emerged involves butyrate having differential effects depending on its concentration and the metabolic state of the cell. Low–moderate concentrations, which are present near the base of colonic crypts, are readily metabolized in the mitochondria to stimulate cell proliferation via energetics. Higher concentrations, which are present near the lumen, exceed the metabolic capacity of the colonocyte. Unmetabolized butyrate enters the nucleus and functions as a histone deacetylase (HDAC) inhibitor that epigenetically regulates gene expression to inhibit cell proliferation and induce apoptosis as the colonocytes exfoliate into the lumen. Butyrate may therefore play a role in normal homeostasis by promoting turnover of the colonic epithelium. Because cancerous colonocytes undergo the Warburg effect, their preferred energy source is glucose instead of butyrate. Consequently, even moderate concentrations of butyrate accumulate in cancerous colonocytes and function as HDAC inhibitors to inhibit cell proliferation and induce apoptosis. These findings implicate a bacterial metabolite with metaboloepigenetic properties in tumor suppression. Clin Cancer Res; 20(4); 799–803. ©2013 AACR.
BIOCHEMICAL STUDIES ON THE VIRUS AND THE INCLUSION BODIES OF SILKWORM JAUNDICE
Authors: R. W. Glaser, W. M. Stanley
Journal: The Journal of Experimental Medicine (1943)

Silkworm jaundice virus is stable only between pH 5 and about pH 9. The fact that polyhedral bodies retain virus activity after exposure to hydrogen ion concentrations as high as pH 2 is regarded as being due to the protection of virus occluded within the bodies. Further evidence on this point is furnished by experiments on the activity of the polyhedra when treated with antiformin-formalin and when treated with 1 per cent sodium dodecyl sulfate. Free jaundice virus is inactivated by 36 per cent urea, 36 per cent guanidine, or 1 per cent sodium dodecyl sulfate. A purified preparation, active at a concentration of 10(-12) gm. per cc., consisting essentially of a nucleoprotein component having a sedimentation constant of 17 S, a particle diameter of 10 mmicro, and a molecular weight of about 300,000, was obtained from the polyhedra-free blood of jaundiced silkworms. However, a component having a sedimentation constant of 16 S was demonstrated in the blood of normal worms. This component, the material from diseased blood, and polyhedral bodies, were found to contain serologically related material. Absorption of material from diseased blood with antiserum induced by a preparation from normal blood yielded a substance having a sedimentation constant of 17 S, which reacted strongly only with antiserum to material from diseased blood. This fact, and especially the fact that the inoculation of normal blood does not produce jaundice, demonstrates that a difference must exist between the purified material from diseased worms and that from normal ones. Chemical analyses of the purified virus material and of the polyhedral bodies also showed certain differences, although both probably represent nucleoproteins. Examination by means of the electron microscope showed further differences.
Vinorelbine, cisplatin and continuous infusion of 5-fluorouracil (ViFuP) in metastatic breast cancer patients: A phase II study
Authors: F. Nolè, E. Munzone, M. Mandalà, C. Catania, L. Orlando, M.G. Zampino, I. Minchella, M. Colleoni, G. Peruzzotti, E. Marrocco, A. Goldhirsch
Journal: Annals of Oncology (2001)
Identification of progastrin derived peptides in colorectal carcinoma extracts.
Authors: J Nemeth, B Taylor, S Pauwels, A Varro, G J Dockray
Journal: Gut (1993)

The possible production of gastrin by colorectal carcinomas has been studied. Extracts of 44 tumours and adjacent macroscopically normal tissue were examined in radioimmunoassay using the following antibodies: (i) L289 raised to a C-terminal fragment of progastrin which shows specificity for intact progastrin, but not the extreme C-terminal tryptic peptide; (ii) LW60 raised to a C-terminal fragment of progastrin which reacts with progastrin and its C-terminal tryptic peptide; (iii) 109-21 which was raised to, and reacts with, Gly-extended forms of heptadecapeptide gastrin--that is, biosynthetic intermediates on the pathway producing active gastrin; and (iv) L2 which reacts with amidated, biologically active gastrins. All samples contained detectable material in assays using LW60; in general, concentrations measured with this antibody were higher than with the other antibodies, and in particular there were higher concentrations in tumour compared with normal tissue extracts. Tumour extracts also contained higher concentrations of immunoreactivity compared with normal tissue, in assays using antibodies L289 and 109-21. In contrast, amidated gastrins were found in similar concentrations in tumour and normal tissue, and concentrations were the lowest of those recorded in the four assays. Separation on Sephadex G50 revealed peaks compatible with progastrin and its C-terminal flanking peptide, and two other peaks that are so far unidentified. In conclusion most colorectal carcinomas contain peptides derived from the gastrin precursor, progastrin, but for the most part these tumours do not convert progastrin into biologically active products.
Anti-CD28 Monoclonal Antibody Therapy Prevents Chronic Rejection of Renal Allografts in Rats
Authors: Igor A. Laskowski, Johann Pratschke, Markus J. Wilhelm, Victor M. Dong, Francisca Beato, Maarten Taal, Martin Gasser, Wayne W. Hancock, Mohamed H. Sayegh, Nicholas L. Tilney
Journal: Journal of the American Society of Nephrology (2002)

ABSTRACT. The effects of a signaling anti-CD28 mAb (JJ319), which interferes with the CD28-B7 T cell costimulation pathway thought to be involved in the development of chronic rejection of organ transplants, was investigated. Functional, morphologic, and molecular changes in rat renal allografts were examined up to 24 wk after placement. Control Lewis rats, recipients of F344 kidneys, received a single dose of a nonspecific mouse mAb intravenously on the day of transplantation (group 1). Group 2 animals were given anti-CD28 mAb in similar fashion. Group 3 animals were treated with a short course of cyclosporin A (CsA), and group 4 received both anti-CD 28 mAb and CsA. The majority (>95%) of animals in groups 2, 3, and 4 survived throughout the follow-up, compared with 28% in group 1 (P < 0.001). Group 2 and 4 recipients produced negligible proteinuria, whereas group 1 controls developed progressively increasing proteinuria after 4 wk and group 3 animals developed proteinuria by 24 wk. Allografts in groups 2 and 4 were morphologically unremarkable at 24 wk. Kidneys of group 1 animals rapidly developed changes of acute rejection, and those that survived long-term showed extensive glomerulosclerosis and interstitial fibrosis. Changes of early chronic rejection were noted in group 3 grafts. By reverse transcriptase–PCR, expression of representative inflammatory factors interferon-γ and interleukin-10 were significantly elevated at 24 wk only in the surviving group 1 animals. A single dose of a signaling anti-CD28 mAb administered at transplantation or in combination with a short course of CsA significantly prolonged recipient survival, normalized function, and preserved the morphology of renal allografts in an established model of chronic rejection. These data support an important role for T cell costimulation in the evolution of the chronic process.
Etanercept during pregnancy and lactation in a patient with rheumatoid arthritis: drug levels in maternal serum, cord blood, breast milk and the infant's serum
Authors: A Murashima, N Watanabe, N Ozawa, H Saito, K Yamaguchi
Journal: Annals of the Rheumatic Diseases (2009)

Women with rheumatoid arthritis (RA) appear to be at a high risk of preterm delivery, preeclampsia and low birth weight infants.1 Reduction of inflammatory activity is of particular importance in those desirous of having children.2 3 The use of disease-modifying antirheumatic drugs, including biological preparations, has been shown to be essential for suppression of the activity of RA. Tumour necrosis factor inhibitors have been introduced for the treatment of RA, with the expectation of obtaining immediate and certain effect. Although no teratogenicity of these drugs has been recognised in animal experiments,4 5 the safety of their use in pregnancy has not yet been adequately established. In this …
Superoxide Dismutase Activity of Normal Murine Liver, Regenerating Liver, and H6 Hepatoma&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: L W Oberley, I B Bize, S K Sahu, S W Leuthauser, H E Gruber
Journal: JNCI Journal of the National Cancer Institute (1978)

By means of both direct assay and gel electrophoresis, normal A/J mouse liver was shown to possess both Cu-Zn and Mn superoxide dismutase (SD) activity. H6 hepatoma cells contained Cu-Zn SD activity, but no Mn SD activity was detectable. Isolated mitochondria from normal liver contained both forms of the enzyme, but isolated mitochondria from H6 hepatoma cells contained no SD activity. To ascertain whether this loss of Mn SD activity was characteristic of these tumor cells or was simply a property of rapidly dividing cells, SD activity was measured in regenerating liver. Mn SD activity was present in the regenerating liver at all times after surgery. Hence loss of the Mn SD activity seemed to be a characteristic of some tumor cells but not of corresponding rapidly dividing normal cells.
Modern Treatment of Rectal Cancer Closes the Gap Between Common Adenocarcinoma and Mucinous Carcinoma
Authors: N. Hugen, C. Van de Velde, S. Bosch, J. Fütterer, M. Elferink, C. Marijnen, H. Rutten, I. Nagtegaal, J. De Wilt
Journal: Annals of Oncology (2014)
Superoxide dismutase prevents the thrombin-induced increase in lung vascular permeability: role of superoxide in mediating the alterations in lung fluid balance.
Authors: A Johnson, M B Perlman, F A Blumenstock, A B Malik
Journal: Circulation Research (1986)

We investigated the effects of superoxide dismutase (SOD) and SOD linked to Ficoll (mol. wt = 400,000) on the changes in pulmonary transvascular fluid and protein exchange following pulmonary microembolism induced with alpha-thrombin. Studies were made in chronically prepared unanesthetized sheep with lung lymph fistulas. Control thrombin challenged sheep (n = 5) were compared to animals infused with SOD (the SOD-thrombin group, n = 5) or animals infused with SOD linked to high molecular weight Ficoll (the Ficoll-SOD-thrombin group, n = 6). The Ficoll-SOD-thrombin animals were also compared to animals infused with Ficoll alone (the Ficoll-thrombin group, n = 4). In the control-thrombin group, thrombin induced sustained increases in the pulmonary transvascular protein clearance (pulmonary lymph flow X lymph/plasma protein concentration ratio) and pulmonary vascular resistance (PVR). In the SOD-thrombin group, thrombin initially increased both pulmonary transvascular protein clearance and PVR; however, the later increases in protein clearance and PVR were blunted. The pulmonary reflection coefficients for total protein (sigma), a measure of vascular permeability to protein, decreased from a value of 0.70 +/- 0.03 in normal sheep to 0.60 +/- 0.01 following thrombin challenge (p less than 0.05) indicating an increase in lung vascular permeability. The sigma value in the SOD-treated animals was 0.70 +/- 0.02, indicating a protective effect of SOD. The infusion of the Ficoll-SOD complex also attenuated the increases in pulmonary transvascular protein clearance and PVR after thrombin. However, the infusion of Ficoll alone induced a similar protection. The lymph from the SOD-thrombin and Ficoll-SOD-thrombin groups prevented the reduction of ferricytochrome C by xanthine/xanthine oxidase, whereas, the lymph from the Ficoll-thrombin animals did not have this effect, indicating SOD activity was present in the animals receiving the enzyme but not in the group infused with Ficoll alone. Differences in the degree of intravascular coagulation could not explain the response to Ficoll since the decreases in fibrinogen concentration following the thrombin were similar in all the groups. Since Ficoll and related dextrans may modify neutrophil function, in particular neutrophil adherence to the endothelium, we examined the effects of Ficoll on neutrophil adherence. The results indicated that when Ficoll was added to the endothelial medium Ficoll reduced the increase adherence of neutrophils to the endothelial cell monolayer. Therefore, Ficoll as a carrier for SOD may provide a direct protection in models of lung vascular injury that are dependent on neutrophils.(ABSTRACT TRUNCATED AT 400 WORDS)
Thrombomodulin Gene Mutations Associated With Myocardial Infarction
Authors: Helen Ireland, Gabriella Kunz, Konstantinos Kyriakoulis, Peter J. Stubbs, David A. Lane
Journal: Circulation (1997)

Background Thrombomodulin is an important receptor for thrombin on the endothelial cell surface of most blood vessels, including those of the heart. Thrombin-bound thrombomodulin activates protein C, which inhibits thrombin generation by degrading factors Va and VIIIa. The aim of this study was to analyze the 5′ region of the thrombomodulin gene to determine whether mutations contribute a risk for myocardial infarction. Methods and Results We screened the promoter region of the thrombomodulin gene by single-stranded conformation polymorphism analysis in 104 patients with diagnosed myocardial infarction. Five mutations (three distinct) were identified (GG−9/−10AT, G−33A, and C−133A). The dinucleotide mutation GG−9/−10AT was identified in 3 individuals (2 heterozygous, 1 homozygous). Only one of the three different mutations was identified in 104 patient control subjects matched for age, sex, and race (G−33A in a single individual). All mutations identified were in close proximity to consensus sequences for transcription control elements within the thrombomodulin gene. In contrast, no difference was observed between patients and control subjects for the allelic frequency of a previously identified neutral polymorphism GCC/GTC coding for Ala/Val 455 , with 3 individuals homozygous for GTC (Val) in both groups. Conclusions The findings suggest that mutations in the promoter region of the thrombomodulin gene may constitute a risk for arterial thrombosis.
Hot of the breath: Mortality as a primary end-point in IPF treatment trials: the best is the enemy of the good
Authors: Athol U Wells, Juergen Behr, Ulrich Costabel, Vincent Cottin, Venerino Poletti, Luca Richeldi
Journal: Thorax (2012)

The problem of the selection of accurate primary end-points for treatment studies in idiopathic pulmonary fibrosis (IPF) has recently been aired in a controversial paper from the USA.1 The limitations of current end-points are discussed and the authors conclude that all-cause mortality and all-cause nonelective hospitalisation best meet clinically meaningful end-point criteria. Much of the article is well argued and there is no quarrel with the view that current primary end-points are flawed. We also agree that all-cause mortality would, indeed, be the most clinically meaningful primary end-point and, therefore, the preferred primary end-point, were it not impractical, as discussed below. However, readers of the statement should reflect on the wise maxim that ‘the best may be the enemy of the good’. The purpose of our document is to provide a perspective on all-cause mortality as a primary end-point, endorsed by 52 European clinicians Including the authors (with one abstention), exploring the implications of the statement by Raghu and colleagues. We believe strongly that the adoption of the views of these authors by licensing bodies—with, by implication, a statistically significant mortality benefit a pre-requisite for drug registration—would set back progress in the treatment of IPF by a decade or more.

It should be acknowledged at the outset that the statement of Raghu and colleagues does not make explicit recommendations with regard to drug licensing. Indeed, the authors declare that it is not their aim to make such recommendations and their intentions in this regard should not be questioned. However, if the statement has, indeed, been widely ‘misread’, the reasons for this are clear enough. Representatives of the US Food and Drug Administration (FDA) were active participants in a forum in Bethesda, Maryland (July 2011) which gave rise to the document as a proceedings statement.1 It is widely known …
Dietary Phosphorus Acutely Impairs Endothelial Function
Authors: Emi Shuto, Yutaka Taketani, Rieko Tanaka, Nagakatsu Harada, Masashi Isshiki, Minako Sato, Kunitaka Nashiki, Kikuko Amo, Hironori Yamamoto, Yukihito Higashi, Yutaka Nakaya, Eiji Takeda
Journal: Journal of the American Society of Nephrology (2009)

Excessive dietary phosphorus may increase cardiovascular risk in healthy individuals as well as in patients with chronic kidney disease, but the mechanisms underlying this risk are not completely understood. To determine whether postprandial hyperphosphatemia may promote endothelial dysfunction, we investigated the acute effect of phosphorus loading on endothelial function in vitro and in vivo. Exposing bovine aortic endothelial cells to a phosphorus load increased production of reactive oxygen species, which depended on phosphorus influx via sodium-dependent phosphate transporters, and decreased nitric oxide production via inhibitory phosphorylation of endothelial nitric oxide synthase. Phosphorus loading inhibited endothelium-dependent vasodilation of rat aortic rings. In 11 healthy men, we alternately served meals containing 400 mg or 1200 mg of phosphorus in a double-blind crossover study and measured flow-mediated dilation of the brachial artery before and 2 h after the meals. The high dietary phosphorus load increased serum phosphorus at 2 h and significantly decreased flow-mediated dilation. Flow-mediated dilation correlated inversely with serum phosphorus. Taken together, these findings suggest that endothelial dysfunction mediated by acute postprandial hyperphosphatemia may contribute to the relationship between serum phosphorus level and the risk for cardiovascular morbidity and mortality.
Comparison of two different pulmonary function test (PFT) interpretive strategies
Authors: Denitza Blagev, Dean Sorenson, Olinto Linares-Perdomo, Stephen Howe, Alan Morris
Journal: European Respiratory Journal (2014)

Background  Although the ratio of FEV1 to vital capacity (VC) is universally accepted as the cornerstone of PFT interpretation, there is disagreement and ambiguity regarding which vital capacity to use.  Objective  To compare how the PFT interpretation changes when the FVC is used in the interpretive algorithm vs. when the largest measured vital capacity VCmaxis used.  Methods  We analyzed 12,239 PFTs from consecutive visits collected as part of routine clinical care between 2001 and 2012. We used our validated electronic decision support tool for PFT interpretation, ePFT, to interpret all tests using two different schemes: once using FVC and again using VCmax.  Results  715 of the 12,239 PFTs (6%) had an interpretation changed based on the algorithm change. The major interpretive changes were as expected: new diagnosis of obstruction and ruling out possible restriction.  Conclusion  The vast majority of PFTs have a stable interpretation regardless of the minor interpretive algorithm change between using VCmax and FVC. However, a minority, 6% do have an interpretive change resulting in new diagnoses of obstruction and exclusion of the diagnosis of restriction.