tbuckley/cabot-search huggingface dataset:
Hepatic autophagy mediates endoplasmic reticulum stress-induced degradation of misfolded apolipoprotein B
Authors: Wei Qiu, Jing Zhang, Mark J. Dekker, Huajin Wang, Ju Huang, John H. Brumell, Khosrow Adeli
Journal: Hepatology (2011)

Abstract Induction of endoplasmic reticulum (ER) stress was previously shown to impair hepatic apolipoprotein B100 (apoB) production by enhancing cotranslational and posttranslational degradation of newly synthesized apoB. Here, we report the involvement of autophagy in ER stress–induced degradation of apoB and provide evidence for a significant role of autophagy in regulating apoB biogenesis in primary hepatocyte systems. Induction of ER stress following short-term glucosamine treatment of McA-RH7777 cells resulted in significantly increased colocalization of apoB with green fluorescent protein–microtubule-associated protein 1 light chain 3 (GFP-LC3), referred to as apoB-GFP-LC3 puncta, in a dose-dependent manner. Colocalization with this autophagic marker correlated positively with the reduction in newly synthesized apoB100. Treatment of McA-RH7777 cells with 4-phenyl butyric acid, a chemical ER stress inhibitor, prevented glucosamine- and tunicamycin-induced increases in GRP78 and phosphorylated eIF2α, rescued newly synthesized [35S]-labeled apoB100, and substantially blocked the colocalization of apoB with GFP-LC3. Autophagic apoB degradation was also observed in primary rat and hamster hepatocytes at basal conditions as well as upon the induction of ER stress. In contrast, this pathway was inactive in HepG2 cells under ER stress conditions, unless proteasomal degradation was blocked with N -acetyl-leucinyl-leucinyl-norleucinal and the medium was supplemented with oleate. Transient transfection of McA-RH7777 cells with a wild-type protein kinase R–like ER kinase (PERK) complementary DNA resulted in dramatic induction of apoB autophagy. In contrast, transfection with a kinase inactive mutant PERK gave rise to reduced apoB autophagy, suggesting that apoB autophagy may occur via a PERK signaling–dependent mechanism. Conclusion: Taken together, these data suggest that induction of ER stress leads to markedly enhanced apoB autophagy in a PERK-dependent pathway, which can be blocked with the chemical chaperone 4-phenyl butyric acid. ApoB autophagy rather than proteasomal degradation may be a more pertinent physiological mechanism regulating hepatic lipoprotein production in primary hepatocytes. (Hepatology 2011;)
Propafenone Treatment of Symptomatic Paroxysmal Supraventricular Arrhythmias
Authors: Edward L.C. Pritchett, Elizabeth A. McCarthy, William E. Wilkinson
Journal: Annals of Internal Medicine (1991)

Objective: To test the hypothesis that propafenone, administered orally, prevents symptomatic paroxysmal supraventricular arrhythmias. Design: A 6-month, open-label, dose-finding phase followed by a randomized, double-blind, placebo-controlled, crossover phase, with each treatment period lasting up to 60 days. Setting: An outpatient clinic. Patients: Thirty-three patients with either paroxysmal supraventricular tachycardia (n = 16) or paroxysmal atrial fibrillation (n =17) were enrolled. Their arrhythmias were documented by electrocardiogram before enrollment. Twenty-three patients (14 with paroxysmal supraventricular tachycardia and 9 with paroxysmal atrial fibrillation) were randomized and the data obtained from these patients were used in the efficacy analysis. Intervention: Propafenone (300 mg three times daily in 19 patients, 300 mg twice daily in 3 patients, and 150 mg twice daily in 1 patient) and matching placebo tablets were administered in a randomized sequence. Measurements: Symptomatic arrhythmia was documented by telephone transmission of the electrocardiogram. Main Results: The time to first recurrence was prolonged for the overall group of 23 patients while they received propafenone (P =0.004). The recurrence rate of arrhythmia during treatment with propafenone was estimated to be approximately one fifth of the recurrence rate during treatment with placebo. Conclusions: Propafenone is effective in reducing symptomatic paroxysmal supraventricular arrhythmias.
Prolonged half‐life of argatroban in patients with renal dysfunction and antiphospholipid antibody syndrome being treated for heparin‐induced thrombocytopenia
Authors: Uzma Athar, Juhi Husain, Jane Hudson, Jennie Lynch, Ajeet Gajra
Journal: American Journal of Hematology (2007)

Abstract Argatroban is a direct thrombin inhibitor approved for the treatment of heparin‐induced thrombocytopenia (HIT) type II. Argatroban is predominantly metabolized in the liver. It is widely believed that no dosage adjustment is required in patients with renal insufficiency, making it a preferred agent in patients on renal replacement therapy (Reddy and Grossman, Ann Pharm 2005;39:1601–1605). The elimination half‐life of argatroban is ∼50 min. Lupus anticoagulants can cause baseline elevation of the PTT and hence it is difficult to monitor the effects of anticoagulants such as heparin, lepirudin, or argatroban in patients with antiphospholipid antibody syndrome. Heparin levels may be used as an alternative for heparin monitoring but plasma levels of argatroban are not commercially available. A chromogenic antifactor IIa assay could be useful for monitoring argatroban in the presence of a lupus anticoagulant, but it is not widely available at present. We report a patient with end‐stage renal disease, maintained on peritoneal dialysis with HIT, who demonstrated a markedly prolonged half‐life when treated with argatroban despite the discontinuation of therapy. This case also demonstrates the lack of guidelines for the monitoring of argatroban therapy in the presence of an underlying lupus anticoagulant. Am. J. Hematol., 2008. © 2007 Wiley‐Liss, Inc.
Intracranial Calcification in Nephrogenic Diabetes Insipidus
Authors: Susumu Kanzaki
Journal: JAMA (1985)

NEPHROGENIC diabetes insipidus (NDI) is a congenital hereditary disorder characterized by insensitivity of the renal tubule to antidiuretic hormone. This congenital hereditary disorder has been associated with a number of central nervous system complications.<sup>1,2</sup>However, intracranial calcification is an extremely rare complication of this disorder.<sup>3</sup>We describe a 2-year-old boy with NDI who presented with a unique pattern of intracranial calcification. Our case shows that NDI may result in organic brain damage if treatment is delayed. <h3>Report of a Case</h3> A boy 2 years 11 months old was admitted to our hospital because of a seizure. He was the product of a normal pregnancy, labor, and delivery of a 30-year-old, gravida 3, para 1, abortus 2 woman. The parents are not related and are of Japanese extraction. His birth weight was 2,900 g. He was given an Apgar score of 9 at both one and five minutes after
Impaired surfactant protein B synthesis in infants with congenital diaphragmatic hernia
Authors: Paola E. Cogo, Manuela Simonato, Olivier Danhaive, Giovanna Verlato, Giovanna Cobellis, Francesco Savignoni, Donatella Peca, Aldo Baritussio, Virgilio P. Carnielli
Journal: European Respiratory Journal (2012)

Pulmonary hypoplasia and hypertension account for significant morbidity and mortality in neonates with congenital diaphragmatic hernia (CDH). Whether CDH is associated with surfactant dysfunction remains controversial. Therefore, we measured disaturated phosphatidylcholine (DSPC) and surfactant protein (SP)-B concentration in tracheal aspirates and their synthesis rate in infants with CDH compared to infants without lung disease. (2)H2O as a precursor of DSPC and 1-(13)C-leucine as a precursor of SP-B were administered to 13 infants with CDH and eight controls matched for gestational age. DSPC and SP-B were isolated from tracheal aspirates, and their fractional synthesis rate was derived from (2)H and (13)C enrichment curves obtained by mass spectrometry. DSPC and SP-B amounts in tracheal aspirates were also measured. In infants with CDH, SP-B fractional synthesis rate and amount were 62±27% and 57±22% lower, respectively, than the value found in infants without lung disease (p<0.01 and p<0.05, respectively). There were no significant group differences in DSPC fractional synthesis rate and amount. Infants with CDH have a lower rate of synthesis of SP-B and less SP-B in tracheal aspirates. In these infants, partial SP-B deficiency could contribute to the severity of respiratory failure and its correction might represent a therapeutic goal.
633. Synergistic Effects of Naked DNA Vectors Encoding VEGF and bFGF on Angiogenesis and Blood Flow Recovery in Ischemic Hindlimb
Authors: Jung-Sun Lee, Jonghoe Byun, Jeong-Min Kim, Chae-Young Kim, Byong-Moon Kim, Ji Hyung Chung, Yangsoo Jang, Duk-Kyung Kim
Journal: Molecular Therapy (2005)

Therapeutic angiogenesis to enhance collateral vessel growth is a promising strategy for the treatment of vascular occlusive diseases. Although local delivery of angiogenic growth factors such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) has shown favorable results, few studies have examined in detail the combined effects of VEGF and bFGF gene delivery on collateral development. Here, we evaluated potential synergism of the naked DNA vectors encoding VEGF and bFGF by using a skeletal muscle-based ex vivo angiogenesis assay and by comparing blood flow recovery and limb loss score in a murine model of hindlimb ischemia (C57BL/6) where femoral artery was excised. In the ex vivo angiogenesis assay, VEGF+bFGF combination group displayed larger sprouting area than LacZ, VEGF, or bFGF group. Reflecting this capillary sprouting data, the combination group had the highest amount of secreted VEGF in the conditioned medium. Consistent with these ex vivo results, regional blood flow recovery at Day 14 as measured by Laser Doppler Imaging was also highest in the VEGF+bFGF combination group followed by bFGF, VEGF, and LacZ control group. The limb loss score was lowest (no necrosis) in the combination group, whereas there were 1|[sim]|4 cases of limb or toe necrosis in other groups. Currently, histological and genetic analyses of the ischemic muscles in the combination group are underway to find the evidence of increased angiogenesis and/or arteriogenesis and upregulation of the genes that may be associated with arteriogenesis, such as cardiac ankyrin repeat protein (CARP), TGF-|[beta]|1, and early growth response factor-1 (Egr-1). Our study has an implication for the development of combined arteriogenic gene therapy that uses the two best characterized angiogenic growth factors, VEGF and bFGF.
Creativity of metaphor in perceptual symbol systems
Authors: Bipin Indurkhya
Journal: Behavioral and Brain Sciences (1999)

A metaphor can often create novel features in an object or a situation. This phenomenon has been particularly hard to account for using amodal symbol systems: although highlighting and downplaying can explain the shift of focus, it cannot explain how entirely new features can come about. We suggest here that the dynamism of perceptual symbol systems, particularly the notion of simulator, provides an elegant account of the creativity of metaphor. The elegance lies in the idea that the creation of new features by a metaphor proceeds in the same way as the creation of regular features in a perceptual symbol.
ABC of the upper gastrointestinal tract: Epidemiology and diagnosis of Helicobacter pylori infection
Authors: R. P H Logan, M. M Walker
Journal: BMJ (2001)

Helicobacter pylori is a small, curved, highly motile, Gram negative bacillus that colonises only the mucus layer of the human stomach. Since its discovery in 1984, it has been recognised as the principal cause of peptic ulcer disease and as the main risk factor for the development of gastric cancer. However, most infected people (>70%) are asymptomatic. We therefore need to discover how infection is acquired, why ulcers or cancer occur in so few of those infected, and how this subgroup can be identified and treated.

H pylori is one of the commonest bacterial pathogens in humans. The prevalence of infection varies but is falling in most developed countries. Seropositivity increases with age and low socioeconomic status. Retrospective seroepidemiological studies have shown a cohort effect consistent with the hypothesis that infection is mainly acquired in early childhood. Until recently, however, it has been difficult to assess accurately the incidence (or route) of infection because of the inaccuracy and cost of detecting (non-invasively) H pylori in young children. Primary acquisition in adults, or reinfection after successful eradication, does occur but is less common, with an annual incidence of 0.3-0.7% in developed countries and 6-14% in developing countries.



Prevalence of H pylori infection by age in developing and developed countries



How H pylori is usually acquired and its route of transmission are unknown. Since humans are the only known reservoir of infection, it is likely that in developed countries H pylori is picked up from siblings, other children, or parents, predominantly via the gastro-oral route. In developing countries faecal-oral transmission may also occur. Various risk factors are associated with H pylori infection, but the extent to which these are simply markers of childhood socioeconomic deprivation is unclear. H pylori infection …
THE INFLUENCE OF DIET UPON THE FORMATION AND HEALING OF ACUTE ULCER OF THE STOMACH
Authors: C. Bolton
Journal: BMJ (1910)

m BUTZ=, X963 ment, and the eyes should not be directly concerned with the gun, but with the object that is being fired at.You require both eyes fixed on the object, in order to judge of its dis.tance, and that is an essential datum for forming a judgement as to the rate at which it is travelling past
S88 Electron Tomography Detects Ultrastructural Abnormalities In Patients With Pcd Due To A Dnah11 Defect
Authors: R. Kwan, T. Burgoyne, M. Dixon, M. Patel, J. Scully, A. Onoufriadis, C. Hogg, H. Mitchison, A. Shoemark
Journal: Thorax (2014)

<h3></h3> Primary Ciliary Dyskinesia (PCD) is a genetically heterogeneous condition. characterised by impaired mucociliary clearance and chronic sino-pulmonary disease. Over 30 causative gene mutations resulting in dysfunctional ciliary motility and structure have been identified. Ciliary ultrastructure examined by Transmission Electron Microscopy (TEM) is currently the diagnostic gold standard. Patients with mutations in the gene <i>DNAH11</i> have a hyperfrequent ciliary beat and clinical symptoms of PCD. Diagnosis of a <i>DNAH11</i> defect by TEM is difficult due to apparently normal ciliary ultrastructure. The electron tomography technique, an extension of TEM, produces 3D models of cilia with superior resolution. The aim of this study was to determine if electron tomography can detect ultrastructural abnormalities in patients with <i>DNAH11</i> defects. Immunofluorescence by specific antibodies for <i>DNAH11</i> showed localisation to the proximal portion of cilia. Proximal cilia cross sections from araldite embedded nasal brush biopsies were examined. Dual axis tomograms were collected on a Philips CM200 electron microscope. The data were analysed using IMOD software and averaged using PEET. Electron tomography and averaging of cilia cross sections indicated a deficiency in the outer dynein arm, consistent across all patients with a <i>DNAH11</i> defect (n = 5) compared to healthy controls (n = 3) and patients with PCD due to a defect of the central pair or nexin link (n = 3) (Figure 1). A reduction in outer dynein arm volume of 30% was identified compared to healthy and PCD controls. In conclusion, a mutation in <i>DNAH11</i> results in a subtle abnormality in ultrastructure. The defects are specific to the ‘forearm’ of the outer dynein arm and only detectable at the base of the cilium where <i>DNAH11</i> is located. Electron tomography is highly effective in visualising this defect.
CHLOROPHYLL AND DEODORIZATION
Authors: Conrad R. Lam
Journal: JAMA (1953)

<h3>To the Editor:—</h3> I was interested in the editorial "Chlorophyll and Deodorization" inThe Journal, Oct. 24, 1953, and the correspondence in the same issue. It is understandable that the wide claims for the deodorizing properties of the agent are being questioned. I think it would be a good idea to question some of the other claims that have been made for chlorophyll preparations, especially those relating to an alleged effect on wound healing. I am not familiar with a single clinical or experimental study that has proved conclusively that chlorophyll is beneficial. It is true that many wounds have healed under a chlorophyll ointment, but no untreated control wounds were provided. During World War II, a burn study unit at the Henry Ford Hospital undertook to evaluate chlorophyll, with wound healing experiments on guinea pigs and in clinical wounds of many types (Lam, C. R., and Brush, B. E.:
Amphibole content of cosmetic and pharmaceutical talcs.
Authors: A M Blount
Journal: Environmental Health Perspectives (1991)

Pharmaceutical and cosmetic-grade talcs were examined for asbestiform amphibole content using a new density-optical method. Talcs under the Food and Drug Administration are not regulated as to asbestos content; however, all talcs were well below the level mandated by the Occupational Safety and Health Administration for industrial talcs. Only one was found to contain an amphibole particle size distribution typical of asbestos.
Distinguishing Depression From Functional Impairment in the Medical Outcomes Study-Reply
Authors: Kenneth B. Wells
Journal: JAMA (1990)

<h3>In Reply.—</h3> Dr Jencks raises important issues regarding (1) the overlap of symptoms of depression with functional status, (2) comparison of patients with depressive symptoms above a specific threshold with medically ill patients without confirmed current symptoms, and (3) differences in case-finding methods. In response, we first discuss the nature of the conditions studied and then comment on each issue. Depression is a condition that is only defined when some symptoms are present; there is no truly asymptomatic depression. Thus, to study the morbidity associated with depression, one must identify persons who are actively depressed. Chronic medical conditions, however, are thought to be ongoing, nonreversible, pathological processes with varying symptom presentation. For such conditions, it makes sense to examine morbidity at any phase of the illness; a study based on only symptomatic cases of hypertension, for example, would not be particularly representative of patients with hypertension. As we noted in
Hepatitis B virus replication in human HepG2 cells mediated by hepatitis B virus recombinant baculovirus
Authors: William E. Delaney, Harriet C. Isom
Journal: Hepatology (1998)

A novel transient mechanism for studying hepatitis B virus (HBV) gene expression and replication using recombinant HBV baculovirus to deliver the HBV genome to HepG2 cells was generated. In HBV baculovirus infected HepG2 cells, HBV transcripts, and intracellular and secreted HBV antigens are produced; replication occurs as evidenced by the presence of high levels of intracellular replicative intermediates and protected HBV DNA in the medium. Density-gradient analysis of extracellular HBV DNA indicated that the DNA was contained predominantly in enveloped HBV virions. Covalently closed circular (CCC) DNA is present indicating that, in this system, HBV core particles are capable of delivering newly synthesized HBV genomes back into the nuclei of infected cells. HBV gene expression is driven exclusively from endogenous promoters. Levels of HBV gene expression and replication can be achieved in HBV baculovirus-infected HepG2 cells which far exceed levels found in HepG2 2.2.15 cells. HBV baculovirus infection of HepG2 cells lends itself readily to experimental manipulation as follows: 1) HBV expression can be initiated any time relative to seeding of HepG2 cells; 2) levels of HBV replication can be regulated over a wide range simply by changing the baculovirus multiplicity of infection; 3) HBV replication is readily detectable by one day post infection with HBV baculovirus and persists at least through day eleven post infection; and (4) the transient nature of the infection can be extended and/or enhanced by superinfecting the cultures. We conclude that infection of HepG2 cells by HBV recombinant baculovirus represents a simple to use and highly flexible system for studying the effects of antivirals and/or cytokines on HBV production and for understanding HBV replication and pathogenesis at the molecular level.
Importation of poliomyelitis to industrialised nations between 1975 and 1984: evaluation and conclusions for vaccination recommendations.
Authors: D Kubli, R Steffen, M Schar
Journal: BMJ (1987)

World Health Organisation and public health authority records show that 175 cases of paralytic poliomyelitis were imported to industrialised countries between 1975 and 1984. Detailed case reports were therefore analysed to identify characteristic features associated with acquisition of the infection. Of the 175 cases, 96 (55%) were diagnosed in foreign workers or their families, 47 (27%) in nationals travelling on holiday or business, 11 (6%) in immigrants, and 21 (12%) either in contacts who had not travelled or in unclassified groups. Poliomyelitis principally affected children under 5, but travellers aged 41-65 had the highest case fatality rate. The main serotype isolated was poliovirus type 1. The findings suggest that though fewer than one in every 100,000 travellers may be infected by poliomyelitis, all travellers and all immigrants, refugees, and foreign workers should be given full protection against all three polioviruses by routine vaccination.
Once Again, Delivered by Hand
Authors: John Lister
Journal: New England Journal of Medicine (1968)

ONE does not need to be in any sense an alcoholic to enjoy the euphoria induced by the gin and tonic dispensed by the air hostess on a transatlantic flight. The deadline of the reporting time at the airport makes it essential to hand over all clinical and other responsibilities with at least temporary finality, if the term is acceptable, and there is a certain sense of relief on boarding the aircraft and abandoning one's destiny to the captain and his crew. Each time there is still a feeling of adventure as the announcements come over the intercom. The tone . . .
The Crisis in Clinical Research: Overcoming Institutional Obstacles
Authors: G. Stephen DeCherney
Journal: JAMA (1993)

Professor Ahrens has written<i>The Crisis in Clinical Research</i>for every clinical scientist struggling against the new scientific consumer. With the skill of a clinical scientist, Professor Ahrens correctly isolates the forces that have made becoming a clinical scientist a frustrating, tedious, and often emotionally painful experience. The opportunities are few, the path is tortuous, and "The mind boggles at who is getting $2 billion in processes perhaps less rigorous than the peer review of the NIH." there are very few breaks along the way. This new scientific consumer places a high value on expediency and immediate results, according to Professor Ahrens. The consumer is part man-in-the-street, part laboratory scientist, part clinician, part university administrator, part legislator. Each demands answers to either project-oriented research or disease-oriented research. What Ahrens calls "basic POR" (patient-oriented research) languishes. He cogently argues that studying pure pathophysiology will be the only way in which we