tbuckley/cabot-search huggingface dataset:
Pili annulati: electron histochemical studies on affected hairs
Authors: C.L. GUMMER, R.P.R. DAWBER
Journal: British Journal of Dermatology (1981)

In this study we have shown that in pili annulati all the normal layers within each cuticle cell are present, and show a normal distribution of cystine. The presence of well ordered macrofibrils, composed of microfibrils embedded in a cystine rich matrix, in both regions of the hair shaft indicates that normal keratinization can and does take place. We have demonstrated the presence of electronopaque, cystine positive material at the intermacrofibrillar spaces and suggest that the presence of the cortical holes is in part due to insufficient cortical material to occupy the space available, and in part due to the dissolution of the intermacrofibrillar material, possibly by water or other chemical agents, diffusing through an apparently more permeable cuticle.
Chronic cough and sputum production: a clinical COPD phenotype?: Table 1–
Authors: Pierre-Régis Burgel
Journal: European Respiratory Journal (2012)

Chronic obstructive pulmonary disease (COPD) is characterised by incompletely reversible airflow limitation and its severity has been categorised using the level of forced expiratory volume in 1 s (FEV1) [1]. Because marked heterogeneity existed between subjects with comparable FEV1 [2], it has been proposed that identification of subgroups of COPD subjects could represent an alternative to the current FEV1-based classification [3]. A consensus report proposed that COPD phenotypes, as defined by “a single or combination of disease attributes that describes differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression or death)”, could represent the future of COPD [4].

Chronic cough and sputum production (chronic bronchitis) have long been recognised as a consequence of tobacco smoking. In the 1960s, the British hypothesis proposed that chronic cough and sputum production encouraged bronchial infection, which promoted airway and alveolar damage and led to airflow limitation [5]. In their classical study reported in 1976, Fletcher and Peto [6] concluded that while chronic cough and sputum production and airflow limitation both occurred in smokers, they were largely unrelated disease processes. Almost 20 yrs later, Vestbo et al . [7] reported that chronic cough and sputum production were associated with an excess FEV1 decline and increased risk of hospitalisation because of COPD. Data from the Lung Health Study further indicated that chronic cough and sputum production were associated with increased lower respiratory illnesses (exacerbations) in subjects with mild airflow limitation [8]. These two studies shed new light on the potential importance of chronic cough and …
Clinical Features and Outcome of Patients With Non–Small-Cell Lung Cancer Who Harbor <i>EML4-ALK</i>
Authors: Alice T. Shaw, Beow Y. Yeap, Mari Mino-Kenudson, Subba R. Digumarthy, Daniel B. Costa, Rebecca S. Heist, Benjamin Solomon, Hannah Stubbs, Sonal Admane, Ultan McDermott, Jeffrey Settleman, Susumu Kobayashi, Eugene J. Mark, Scott J. Rodig, Lucian R. Chirieac, Eunice L. Kwak, Thomas J. Lynch, A. John Iafrate
Journal: Journal of Clinical Oncology (2009)

The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK.Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing.Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival.EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.
The profilaggrin N-terminal domain is absent in pityriasis rotunda
Authors: K. Yoneda, R.B. Presland, T. Demitsu, T. Shimizu, Y. Kubota
Journal: British Journal of Dermatology (2011)

Funding sources: this work was in part supported by grants from the Ministries of Health, Labour and Welfare, and Education, Culture, Sports, Science and Technology of Japan. Conflicts of interest: none declared. Madam, Pityriasis rotunda (PR) is a rare keratinizing disorder characterized by round or oval patches that are hyper‐ or hypopigmented, well‐demarcated plaques.1 The main lesional sites are trunk and extremities. This disease entity was initially described in Japan by Toyama in 1906 and was termed tinea circinata.1 This keratinizing disorder has frequently been reported in Japan, South Africa and the West Indies.2, 3 The incidence in caucasian populations appears to be very low. The aetiology of PR is at present unknown. There are several reports that suggest that PR is a form of acquired ichthyosis, a delayed form of congenital ichthyosis, or a skin manifestation of systemic disease.2, 3 Filaggrin is crucial in the formation of the stratum corneum. At the time of terminal differentiation of granular keratinocytes, the 400‐kDa protein profilaggrin is proteolytically cleaved into ∼37‐kDa filaggrin peptides and the profilaggrin N‐terminal domain (PND) containing the S100‐like calcium binding domain.4 Hashimoto et al.5 reported that there was a marked decrease in filaggrin and loricrin expression in PR. Here, we describe a Japanese patient with PR, whose skin lesion showed diminished expression of the PND. We also examined the distribution of filaggrin and loricrin6 in the involved skin of our patient.
Impaired Hyperglycemia-Induced Delay in Gastric Emptying in Patients With Type 1 Diabetes Deficient for Islet Amyloid Polypeptide
Authors: Hans J. Woerle, Max Albrecht, Rainer Linke, Silvia Zschau, Christoph Neumann, Mathias Nicolaus, John E. Gerich, Burkhard Göke, Joerg Schirra
Journal: Diabetes Care (2008)

Slowing of gastric emptying by hyperglycemia, a physiological response to minimize postprandial hyperglycemia, may be impaired in patients with type 1 diabetes. The causes and consequences on glucose homeostasis are unknown.Consequences of euglycemia- and hyperglycemia-induced changes in gastric emptying on postprandial glucose fluxes and excursions were studied in 10 healthy subjects and 15 type 1 diabetic subjects after ingestion of a mixed meal using the double isotope approach ([6,6-(2)H(2)] and [1-(13)C]glucose) and scintigraphic measurements of gastric emptying.Gastric emptying was greater in type 1 diabetic subjects (90-120 min, P < 0.03), and 50% retention times were comparable in healthy subjects and type 1 diabetic subjects (167 +/- 8 vs. 152 +/- 10, P = 0.32). Hyperglycemia markedly delayed gastric emptying in healthy subjects but did not alter it in type 1 diabetic subjects (50% retention time 222 +/- 18 vs. 167 +/- 8 min, P = 0.003 and 148 +/- 9 vs. 152 +/- 10 min, P = 0.51). Plasma islet amyloid polypeptide (IAPP) increased approximately fourfold in healthy subjects (P < 0.001), whereas it was undetectable in type 1 diabetic subjects. IAPP replacement, using the analog pramlintide, in type 1 diabetic subjects slowed gastric emptying to a comparable extent, as did hyperglycemia in healthy subjects (P < 0.14), and greatly reduced postprandial hyperglycemia (P < 00.1). Meal-derived glucose appearance in plasma (10.7 +/- 0.5 vs. 6.8 +/- 0.7 mumol . kg(-1) . min(-1), P < 0.001) was reduced, and splanchnic glucose sequestration increased (14.0 +/- 3.0 vs. 25.0 +/- 6.0%, P = 0.04).In patients with type 1 diabetes the ability to delay gastric emptying in response to hyperglycemia is impaired. This impairment contributes to exaggerated rates of meal-derived glucose appearance and, ultimately, postprandial glucose excursions.
Domiciliary comparison of terbutaline treatment by metered dose inhaler with and without conical spacer in severe and moderately severe chronic asthma.
Authors: J F O'Reilly, G Gould, A H Kendrick, G Laszlo
Journal: Thorax (1986)

The bronchodilator response to cumulative doses of terbutaline administered by metered dose inhaler with and without a conical spacer device and by Acorn nebuliser has been compared in groups of patients with chronic severe and moderately severe asthma. After laboratory studies the patients undertook a randomised domiciliary crossover comparison of bronchodilator response to terbutaline given by metered dose inhaler with and without a spacer device, during which the severity of asthma was assessed by thrice daily recordings of peak expiratory flow (PEF) and symptom score. Improvement in FEV1 produced in the laboratory by the metered dose inhaler with spacer device was significantly greater than by metered dose inhaler alone (p less than 0.001) and similar to that from the nebuliser in both asthmatic groups throughout a range of terbutaline doses. In the domiciliary comparison mean midday and evening PEF rates were significantly higher with the use of the spacer device both in those with severe (p less than 0.01) and in those with moderately severe (p less than 0.05) asthma, and mean morning PEF was significantly higher in the severe group (p less than 0.05). The spacer device also produced a significant improvement in symptom score in both the severe and the moderately severe groups (p less than 0.05). Regular domiciliary use of the spacer device with the metered dose inhaler improves bronchodilator response, particularly in patients with chronic severe asthma, and may be a useful alternative to nebuliser treatment.
Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: Results of a randomized trial
Authors: Keith D. Lindor, Kris V. Kowdley, Jenny E. Heathcote, Edwyn M. Harrison, Roberta Jorgensen, Paul Angulo, James F. Lymp, Lawrence Burgart, Patrick Colin
Journal: Hepatology (2004)

No effective medical therapy is available for all patients with nonalcoholic steatohepatitis (NASH). Ursodeoxycholic acid (UDCA) has been suggested to be of benefit based on open label clinical studies. We randomized 166 patients with liver biopsy-proven NASH to receive between 13 and 15 mg/kg/d of UDCA or placebo for 2 years. End points included changes in liver test results and liver histology at 2 years of therapy. The treatment groups were comparable at entry with regard to age, gender, risk factors for NASH, serum liver biochemistries, and baseline liver histology. A total of 126 patients completed 2 years of therapy. Pre- and posttreatment liver biopsies were available in 107 patients for review at the end of the study. UDCA was well tolerated and body weight was stable during the study duration. Serum liver biochemistries were stable or improved in both the UDCA and placebo-treated groups. Changes in the degree of steatosis, necroinflammation, or fibrosis that occurred with therapy were not significantly different between the UDCA and placebo groups. In conclusion, 2 years of therapy with UDCA at a dose of 13 to 15 mg/kg/d, although safe and well tolerated, is not better than placebo for patients with NASH.
Role of the vascular and lymphatic endothelium in the pathogenesis of inflammatory bowel disease: 'brothers in arms'
Authors: S. Danese
Journal: Gut (2011)

The ‘IN’ of chronic inflammation—that is, the mechanisms of cell entry into the intestinal mucosa, bacterial and foreign antigen invasion, angiogenesis, and the control of gut inflammation through intestinal microvasculature—has received a great deal of attention in studies of the pathogenesis of inflammatory bowel disease (IBD). This has resulted in the validation of several targets for the treatment of experimental inflammation—both on immune and non-immune cells—some of which have translated into effective treatments for patients with IBD. An important aspect of this has been our growing understanding of the role the intestinal vascular microcirculation plays in the initiation and perpetuation of the inflammatory process, by regulating the migration of leucocytes into the interstitial space. However, it is becoming increasingly clear that it is also important to focus on the ‘OUT’ of chronic inflammation—that is, the lymphatics and their role in controlling tissue oedema, leucocyte exit, bacterial antigen and inflammatory chemokine clearance. As our understanding of the lymphatics and the role they play grows, another rich source of non-immune cell targets for therapeutic intervention is gradually being revealed. This article describes current knowledge of the roles played by the vascular and lymphatic endothelium throughout the gut in the pathogenesis of IBD, and how this differs from their role under physiological conditions, as well as discussing current and future therapeutic targets that have been identified.
Thioredoxin, a Redox Enzyme Released in Infection and Inflammation, Is a Unique Chemoattractant for Neutrophils, Monocytes, and T Cells
Authors: Riccardo Bertini, O.M. Zack Howard, Hui-Fang Dong, Joost J. Oppenheim, Cinzia Bizzarri, Rita Sergi, Gianfranco Caselli, Sabrina Pagliei, Brie Romines, Jennifer A. Wilshire, Manuela Mengozzi, Hajime Nakamura, Junji Yodoi, Klas Pekkari, Ramanathan Gurunath, Arne Holmgren, Leonore A. Herzenberg, Leonard A. Herzenberg, Pietro Ghezzi
Journal: The Journal of Experimental Medicine (1999)

Thioredoxin (Trx) is a ubiquitous intracellular protein disulfide oxidoreductase with a CXXC active site that can be released by various cell types upon activation. We show here that Trx is chemotactic for monocytes, polymorphonuclear leukocytes, and T lymphocytes, both in vitro in the standard micro Boyden chamber migration assay and in vivo in the mouse air pouch model. The potency of the chemotactic action of Trx for all leukocyte populations is in the nanomolar range, comparable with that of known chemokines. However, Trx does not increase intracellular Ca2+ and its activity is not inhibited by pertussis toxin. Thus, the chemotactic action of Trx differs from that of known chemokines in that it is G protein independent. Mutation of the active site cysteines resulted in loss of chemotactic activity, suggesting that the latter is mediated by the enzyme activity of Trx. Trx also accounted for part of the chemotactic activity released by human T lymphotropic virus (HTLV)-1–infected cells, which was inhibited by incubation with anti-Trx antibody. Since Trx production is induced by oxidants, it represents a link between oxidative stress and inflammation that is of particular interest because circulating Trx levels are elevated in inflammatory diseases and HIV infection.
Correlation of Insulin-Like Growth Factor-Binding Protein-3 Messenger RNA With Protein Expression in Primary Breast Cancer Tissues: Detection of Higher Levels in Tumors With Poor Prognostic Features
Authors: R. L. Rocha, S. G. Hilsenbeck, J. G. Jackson, A. V. Lee, J. A. Figueroa, D. Yee
Journal: JNCI Journal of the National Cancer Institute (1996)

Background:The insulin-like growth factor (IGF)-binding proteins (IGFBPs) regulate the actions of the IGFs by influencing interactions between the IGFs and the IGF receptors. IGFBP-3, one of the six known species of IGFBPs, is the predominant IGFBP in serum and is expressed by breast cancer cells. Compared with estrogen receptor (ER)-positive samples, ER-negative breast cancer cell lines and tumors express higher levels of IGFBP-3. Therefore, expression of IGFBP-3 may be relevant in breast cancer biology, although it is unknown whether IGFBP-3 levels correlate with other breast cancer prognostic factors besides ER status. It is also not known how different methods used to measure IGFBP-3 in breast cancer correlate.
Voltage-gated calcium-channels and antiarrhythmic drug action
Authors: A Grace
Journal: Cardiovascular Research (2000)

Calcium-channels, blockers have an established role in the management of cardiac arrhythmias [1–5]. They were identified empirically with the idea of achieving selective inhibition of voltage-gated calcium-channels and vasodilatation [6,7], but early laboratory studies of the hemodynamic and vascular effects of verapamil happened also to demonstrate efficacy against cardiac arrhythmias [1,8]. The importance of the landmark paper by Vaughan Williams and Singh [9] is that it proposed a novel discrete mechanism for the drug control of arrhythmias that did not rely on the three mechanisms viz. local anaesthetic, anti-sympathetic or delay in repolarization already described [10]. There were two major outcomes of this publication. First, the expanded and refined classification of antiarrhythmic drug actions heralded a period of development in antiarrhythmic drug strategies and encouraged critical thinking about the mechanisms of drug action. This contributed in turn to a more complete evaluation of antiarrhythmic drug therapy in general [11,12]. Second, intravenous verapamil entered clinical practice leading to a complete change in the treatment of acute paroxysmal supraventricular tachycardia [13–15]. The deployment of calcium-channel blockers in cardiac arrhythmias moved, of course, in parallel with increased use of this class of drug in coronary artery disease and hypertension [16,17]. This growth was unencumbered until more recently when it has been clouded by controversy [17–21].

This commentary will examine the cellular and molecular mechanisms of action and current applications of calcium-channel blockers in cardiac arrhythmias. We contend that there have been major advances in understanding the molecular mechanisms of action of these agents and this has substantially contributed to a greatly expanded knowledge of cardiac (and indeed non-cardiac) ion channel structure-function relationships [22]. This explosion of knowledge however has not yet resulted in any useful new drugs [23]. Despite this lack of progress …
Purification and characterization of a mannose-containing disaccharide obtained from human pregnancy urine. A new immunoregulatory saccharide.
Authors: A V Muchmore, J M Decker, R M Blaese, B Nilsson
Journal: The Journal of Experimental Medicine (1984)

Endogenous mammalian lectin-like sugar-binding molecules have been previously described that have immunoregulatory properties. Further, the addition of defined simple saccharides to lymphocyte cultures has been shown to inhibit a variety of in vitro lymphocyte functions, presumably because these sugars are able to compete with the binding of endogenous lectins to critical membrane receptors. In this report, we describe the isolation and characterization of a D-mannose-containing disaccharide in human pregnancy urine that inhibits the proliferative response of human T lymphocytes. The inhibitory disaccharide was purified to homogeneity by sequential steps including affinity chromatography on immobilized concanavalin A and molecular sizing on Sephadex G-75 and then Fractogel 40S columns, with final purification on high-performance thin-layer chromatography. By mass spectrometry of the purified material as its permethylated derivative, the deduced structure of this compound was alpha-D-Manp 1-6-D-Man. To confirm that this disaccharide was in fact immunosuppressive, an identical disaccharide was prepared by sequential digestion of yeast cell wall polysaccharide. The urinary and yeast disaccharides had identical immunosuppressive properties. It has been previously reported that D-mannose is inhibitory for antigen-specific proliferative assays in the range of 10-50 mM. The purified alpha-D-Manp 1-6-D-Man disaccharide was inhibitory at 100-fold-lower concentrations. Further, while D-mannose inhibits T cell proliferation when added at anytime up to 24 h before harvest of a 6-d lymphocyte culture, alpha-D-Manp 1-6-D-Man disaccharide was inhibitory only if added at the initiation of culture and had no inhibitory effect if added just 24 h later. These data support the concept that simple sugar compounds can exhibit marked immunoregulatory activity in vitro. The impact of these molecules on the regulation of immune responses in vivo is unknown, as is their precise mechanism of action, but structural and chemical identification should now permit a detailed analysis of these issues.
<i>Salmonella</i>-Induced Apoptosis of Infected Macrophages Results in Presentation of a Bacteria-Encoded Antigen after Uptake by Bystander Dendritic Cells
Authors: Ulf Yrlid, Mary Jo Wick
Journal: The Journal of Experimental Medicine (2000)

Salmonella typhimurium is a gram-negative bacterium that survives and replicates inside vacuolar compartments of macrophages. Infection of macrophages with S. typhimurium grown under conditions allowing expression of the type III secretion system results in apoptotic death of the infected cells. Here, we show that infection of bone marrow–derived macrophages (MΦ) with wild-type S. typhimurium 14028 results in presentation of epitopes derived from a bacteria-encoded antigen on major histocompatibility complex (MHC) class I and MHC class II molecules after internalization of apoptotic MΦ by bystander dendritic cells (DCs). In contrast, infection of MΦ with the phoP constitutive mutant strain CS022, which does not induce apoptosis in infected MΦ, does not result in presentation of a bacteria-derived antigen by bystander DCs unless the infected MΦ are induced to undergo apoptosis by treatment with lipopolysaccharide and ATP. DCs appear to be unique in their ability to present antigens derived from MΦ induced to undergo apoptosis by Salmonella, as bystander MΦ are not capable of presenting the bacteria-derived antigen despite the fact that they efficiently internalize the apoptotic cells. These data suggest that apoptosis induction by bacterial infection of MΦ may not be a quiescent death that allows the bacteria to escape recognition by the immune system, but rather may contribute to an antimicrobial immune response upon engulfment by bystander DCs.
Predicted strain coverage of a meningococcal multicomponent vaccine (4CMenB) in Europe: a qualitative and quantitative assessment
Authors: Ulrich Vogel, Muhamed-Kheir Taha, Julio A Vazquez, Jamie Findlow, Heike Claus, Paola Stefanelli, Dominique A Caugant, Paula Kriz, Raquel Abad, Stefania Bambini, Anna Carannante, Ala Eddine Deghmane, Cecilia Fazio, Matthias Frosch, Giacomo Frosi, Stefanie Gilchrist, Marzia M Giuliani, Eva Hong, Morgan Ledroit, Pietro G Lovaglio, Jay Lucidarme, Martin Musilek, Alessandro Muzzi, Jan Oksnes, Fabio Rigat, Luca Orlandi, Maria Stella, Danielle Thompson, Mariagrazia Pizza, Rino Rappuoli, Davide Serruto, Maurizio Comanducci, Giuseppe Boccadifuoco, John J Donnelly, Duccio Medini, Ray Borrow
Journal: The Lancet Infectious Diseases (2013)