tbuckley/cabot-search huggingface dataset:
Influence of external pH on ciliary beat frequency in human bronchi and bronchioles
Authors: C Clary-Meinesz, J Mouroux, J Cosson, P Huitorel, B Blaive
Journal: European Respiratory Journal (1998)

Ciliated respiratory epithelial cells have to tolerate variations in local pH caused by the respiratory cycle and potential ventilation-perfusion mismatches. We showed previously that peripheral bronchiolar cilia beat at a lower frequency than bronchial cilia, and have now investigated whether they show differences in tolerance to changes in pH. Using the image analysis system applied in the previous study, we compared variations in the ciliary beat frequencies (CBF) of bronchi and bronchioles sampled from human lung resections at various pH in vitro. Application of nonparametric tests (the variance of samples was not similar) indicated that CBF was not significantly modified when pH was varied between 7.5 and 10.5 for bronchi, and between 5.5 and 10.5 for bronchioles. Reversible and significantly lower CBF were observed below pH 7.0 for bronchi and below pH 5.0 for bronchioles. Extreme pH values such as 11.0 or 3.0 were lethal within a few minutes. Thus, respiratory ciliary beating is able to tolerate external pH variations between 3.5 and 10.5 without permanent impairment. In addition we found that alkaline pH values are more favourable than acidic ones and that bronchiolar ciliated cells are more tolerant to acidic pH than bronchial cells.
Newcastle disease virus-infected splenocytes express the proopiomelanocortin gene.
Authors: H J Westly, A J Kleiss, K W Kelley, P K Wong, P H Yuen
Journal: The Journal of Experimental Medicine (1986)

Infection of murine splenocytes with Newcastle disease virus results in expression of the proopiomelanocortin gene as determined by dot and northern blot analysis of total cellular and poly(A)+ cytoplasmic RNA. These data provide the first evidence that the precursor protein for adrenocorticotropin and beta-endorphin can be synthesized by lymphoid cells.
Seroprevalence of Antibody Against Poliovirus in Inner-city Preschool Children
Authors: R T Chen, S Hausinger, A S Dajani, M Hanfling, A L Baughman, M A Pallansch, P A Patriarca
Journal: JAMA (1996)

<h3>Objective.</h3> —To assess susceptibility to poliomyelitis in selected inner-city preschool children in the United States and to estimate the contribution of secondary spread of live attenuated oral poliovirus vaccine virus to type-specific immunity. <h3>Design.</h3> —Cross-sectional seroprevalence study. <h3>Methods.</h3> —Serum neutralizing antibody levels against poliovirus types 1,2, and 3 were analyzed according to vaccination status, age, and other sociodemographic variables. <h3>Setting.</h3> —Hospital and satellite clinics serving inner-city populations in Houston, Tex, and Detroit, Mich, 1990 to 1991. <h3>Participants.</h3> —A total of 526 children aged 12 to 47 months seeking medical care were enrolled in the seroprevalence study; 144 children aged 12 to 35 months without a history of previous oral poliovirus vaccination were enrolled in the secondary spread study. <h3>Results.</h3> —Seropositive rates were similar in children in both cities, ranging from about 80% for types 1 and 3 in 12- to 23-month-old children to more than 90% in those aged 36 to 47 months. The most important predictor of seropositivity was the number of doses of oral poliovirus vaccine received (<i>P</i>&lt;.01), with levels approximately 90% for all 3 serotypes among children who had received 3 or more doses. In children likely to have been unvaccinated, seropositive rates ranged from 9% to 18% for poliovirus types 1 and 3 and from 29% to 42% for type 2; secondary spread of vaccine virus appeared to have occurred among children who had previously received 1 dose or less but not those with 2 or more doses. <h3>Conclusions.</h3> —Levels of immunity to poliovirus among inner-city preschoolers are high and may be predicted by the number of doses of oral poliovirus vaccine received. Secondary spread of the vaccine virus plays a modest role in increasing polio immunity in inner-city populations, especially against types 1 and 3. This role will decrease in importance if the recently attained high levels of immunization coverage in the United States are sustained and if the risk of importation of wild poliovirus continues to diminish. (<i>JAMA</i>. 1996;276:1639-1645)
Nanotoxicology: An Emerging Discipline Evolving from Studies of Ultrafine Particles
Authors: Günter Oberdörster, Eva Oberdörster, Jan Oberdörster
Journal: Environmental Health Perspectives (2005)

Although humans have been exposed to airborne nanosized particles (NSPs; < 100 nm) throughout their evolutionary stages, such exposure has increased dramatically over the last century due to anthropogenic sources. The rapidly developing field of nanotechnology is likely to become yet another source through inhalation, ingestion, skin uptake, and injection of engineered nanomaterials. Information about safety and potential hazards is urgently needed. Results of older biokinetic studies with NSPs and newer epidemiologic and toxicologic studies with airborne ultrafine particles can be viewed as the basis for the expanding field of nanotoxicology, which can be defined as safety evaluation of engineered nanostructures and nanodevices. Collectively, some emerging concepts of nanotoxicology can be identified from the results of these studies. When inhaled, specific sizes of NSPs are efficiently deposited by diffusional mechanisms in all regions of the respiratory tract. The small size facilitates uptake into cells and transcytosis across epithelial and endothelial cells into the blood and lymph circulation to reach potentially sensitive target sites such as bone marrow, lymph nodes, spleen, and heart. Access to the central nervous system and ganglia via translocation along axons and dendrites of neurons has also been observed. NSPs penetrating the skin distribute via uptake into lymphatic channels. Endocytosis and biokinetics are largely dependent on NSP surface chemistry (coating) and in vivo surface modifications. The greater surface area per mass compared with larger-sized particles of the same chemistry renders NSPs more active biologically. This activity includes a potential for inflammatory and pro-oxidant, but also antioxidant, activity, which can explain early findings showing mixed results in terms of toxicity of NSPs to environmentally relevant species. Evidence of mitochondrial distribution and oxidative stress response after NSP endocytosis points to a need for basic research on their interactions with subcellular structures. Additional considerations for assessing safety of engineered NSPs include careful selections of appropriate and relevant doses/concentrations, the likelihood of increased effects in a compromised organism, and also the benefits of possible desirable effects. An interdisciplinary team approach (e.g., toxicology, materials science, medicine, molecular biology, and bioinformatics, to name a few) is mandatory for nanotoxicology research to arrive at an appropriate risk assessment.
Cigarette smoking, disease severity and autoantibody expression in African Americans with recent-onset rheumatoid arthritis
Authors: T R Mikuls, L B Hughes, A O Westfall, V M Holers, L Parrish, D van der Heijde, M van Everdingen, G S Alarcon, D L Conn, B Jonas, L F Callahan, E A Smith, G Gilkeson, G Howard, L W Moreland, S L Bridges
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To examine the association of smoking with clinical and serological features in African Americans with recent-onset rheumatoid arthritis (RA) and to explore whether this association is dependent on the presence of the <i>HLA-DRB1</i> shared epitope (SE). <h3>Methods:</h3> In African Americans with recent-onset RA (n = 300), we examined the association of cigarette smoking (current versus past versus never and pack-years of exposure) with anti-cyclic citrullinated peptide antibody, rheumatoid factor (RF) (IgM and IgA), rheumatoid nodules and baseline radiographic erosions using logistic and cumulative logistic regression (adjusting for SE status). We also examined for evidence of interaction between smoking status and SE for all outcomes. <h3>Results:</h3> Although there was no association with RF-IgA seropositivity, current smokers were approximately twice as likely as never smokers to have higher IgA-RF concentrations (based on tertiles; OR = 1.74; 95% CI 1.05 to 2.88) and nodules (OR = 2.43; 95% CI 1.13 to 5.22). These associations were most pronounced in those with more than 20 pack-years of exposure. There was no association of smoking status or cumulative tobacco exposure with anti-cyclic citrullinated peptide antibody, IgM-RF or radiographic erosions. There was also no evidence of a biological or statistical SE–smoking interaction for any of the outcomes examined. <h3>Conclusions:</h3> This is the first study to systematically examine the association of cigarette smoking with RA-related features in African Americans. Cigarette smoking is associated with both subcutaneous nodules and higher serum concentrations of IgA-RF in African Americans with RA, associations that may have important implications for long-term outcomes in this population.
Defining an Antigenic Epitope on Platelet Factor 4 Associated With Heparin-Induced Thrombocytopenia
Authors: L. Ziporen, Z.Q. Li, K.S. Park, P. Sabnekar, W.Y. Liu, G. Arepally, Y. Shoenfeld, T. Kieber-Emmons, D.B. Cines, M. Poncz
Journal: Blood (1998)
Haploinsufficiency for the erythroid transcription factor KLF1 causes hereditary persistence of fetal hemoglobin
Authors: Joseph Borg, Petros Papadopoulos, Marianthi Georgitsi, Laura Gutiérrez, Godfrey Grech, Pavlos Fanis, Marios Phylactides, Annemieke J M H Verkerk, Peter J van der Spek, Christian A Scerri, Wilhelmina Cassar, Ruth Galdies, Wilfred van IJcken, Zeliha Özgür, Nynke Gillemans, Jun Hou, Marisa Bugeja, Frank G Grosveld, Marieke von Lindern, Alex E Felice, George P Patrinos, Sjaak Philipsen
Journal: Nature Genetics (2010)
Respiratory Disease in Coal Miners
Authors: W. Keith C. Morgan
Journal: JAMA (1975)

LAST year the Social Security Administration disbursed more than $1 billion for "black lung" compensation. By way of comparison, for 1971 the total disbursement for all other industrial injury and illness for the entire US population covered by workmen's compensation laws was only $2.4 billion. Yet, there are around 120,000 working coal miners as compared to approximately 30 to 40 million other US workers covered by workmen's compensation laws. Nor can this disparity be explained by the fact that a disabled miner receives almost twice as much in compensation as does a disabled steelworker with silicosis. The Federal Coal Mine Health and Safety Act of 1969, and the regulations that were put into effect as the result of the passage of this act, enabled any coal miner to qualify for "black lung" benefits provided he had (1) roentgenographic evidence of complicated pneumoconiosis (progressive massive fibrosis [PMF]); (2) simple pneumoconiosis in
Lymphomas presenting as histologically unclassified neoplasms: characteristics and response to treatment.
Authors: S J Horning, E K Carrier, R V Rouse, R A Warnke, S A Michie
Journal: Journal of Clinical Oncology (1989)

Malignant lymphoma is frequently diagnosed when immunohistochemical techniques are applied to otherwise unclassified neoplasms. In this analysis of 35 patients with a histologically unclassified neoplasm that expressed leukocyte-common antigen(s) (LCA), actuarial survival was 63%, and 45% of patients were free from disease progression at 30 months following treatment as for lymphoma. The clinical features at diagnosis and the results of combination chemotherapy were found to be similar to a group of patients with a diagnosis of diffuse large-cell lymphoma (DLCL) concurrently treated at this institution. This study further emphasizes the importance of improved diagnostic techniques in the management of histologically unclassified tumors.
FBXW7 Mutations in Melanoma and a New Therapeutic Paradigm
Authors: Iraz T. Aydin, Rachel D. Melamed, Sarah J. Adams, Mireia Castillo-Martin, Ahu Demir, Diana Bryk, Georg Brunner, Carlos Cordon-Cardo, Iman Osman, Raul Rabadan, Julide Tok Celebi
Journal: JNCI Journal of the National Cancer Institute (2014)

Melanoma is a heterogeneous tumor with subgroups requiring distinct therapeutic strategies. Genetic dissection of melanoma subgroups and identification of therapeutic agents are of great interest in the field. These efforts will ultimately lead to treatment strategies, likely combinatorial, based on genetic information.To identify "driver" genes that can be targeted therapeutically, we screened metastatic melanomas for somatic mutations by exome sequencing followed by selecting those with available targeted therapies directed to the gene product or its functional partner. The FBXW7 gene and its substrate NOTCH1 were identified and further examined. Mutation profiling of FBXW7, biological relevance of these mutations and its inactivation, and pharmacological inhibition of NOTCH1 were examined using in vitro and in vivo assays.We found FBXW7 to be mutated in eight (8.1%) melanoma patients in our cohort (n = 103). Protein expression analysis in human tissue samples (n = 96) and melanoma cell lines (n = 20) showed FBXW7 inactivation as a common event in melanoma (40.0% of cell lines). As a result of FBXW7 loss, we observed an accumulation of its substrates, such as NOTCH1. Ectopic expression of mutant forms of FBXW7 (by 2.4-fold), as well as silencing of FBXW7 in immortalized melanocytes, accelerated tumor formation in vivo (by 3.9-fold). Its inactivation led to NOTCH1 activation, upregulation of NOTCH1 target genes (by 2.6-fold), and promotion of tumor angiogenesis and resulted in tumor shrinkage upon NOTCH1 inhibition (by fivefold).Our data provides evidence on FBXW7 as a critical tumor suppressor mutated and inactivated in melanoma that results in sustained NOTCH1 activation and renders NOTCH signaling inhibition as a promising therapeutic strategy in this setting.
Polyclonal <i>Mycobacterium avium</i> Complex Infections in Patients with Nodular Bronchiectasis
Authors: RICHARD J. WALLACE, YANSHENG ZHANG, BARBARA A. BROWN, DAVID DAWSON, DAVID T. MURPHY, REBECCA WILSON, DAVID E. GRIFFITH
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Mycobacterium avium complex (MAC) isolates among patients with chronic lung disease were studied for their heterogeneity using genetic identification methods, pulsed field gel electrophoresis (PFGE) and seroagglutination. A mean of 7.3 cultures per patient were collected from 17 patients with nodular bronchiectasis who were elderly (mean age 66 yr), predominantly female (76%), had smoked a mean of only 5 pack-years, and had multifocal bronchiectasis. A mean of 7.7 cultures per patient were collected from nine patients with upper lobe cavitary disease who were younger (mean age 52 yr), predominantly male (78%), and heavy smokers (mean 56 pack-yr). A mean of 2.9 PFGE types (genotypes) per patient (range, 1 to 9) were identified in the nodular bronchiectasis group, with 15 of 17 patients (88%) having two or more genotypes and 9 of 17 (53%) having three or more genotypes. In contrast a mean of 1.2 genotypes were identified in the patients with cavitary disease, with only 1 of 9 (11%) having two or more genotypes. Mycobacterium intracellulare was the most frequently recovered genotype in both groups and most isolates were rough or nontypable by seroagglutination. Some genotypes from the same patient considered different by current PFGE criteria had the same serotype and shared 11 to 20 common PFGE bands, suggesting they were related. These data demonstrate that patients with nodular bronchiectasis have multiple and/or repeated infections due to MAC whereas patients with upper lobe cavitary disease are usually infected with only a single strain.
Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study
Authors: Salim Yusuf, Steven Hawken, Stephanie Ôunpuu, Tony Dans, Alvaro Avezum, Fernando Lanas, Matthew McQueen, Andrzej Budaj, Prem Pais, John Varigos, Liu Lisheng
Journal: The Lancet (2004)
Decreased hyaluronan in airway smooth muscle cells from patients with asthma and COPD
Authors: I. Klagas, S. Goulet, G. Karakiulakis, J. Zhong, M. Baraket, J. L. Black, E. Papakonstantinou, M. Roth
Journal: European Respiratory Journal (2009)

Glycosaminoglycans (GAG) are essential extracellular matrix molecules which regulate tissue flexibility, a parameter that is reduced in airways of patients with asthma and chronic obstructive pulmonary disease (COPD). We investigated the expression of GAG and their metabolising enzymes in primary human airway smooth muscle cells (ASMC) obtained from healthy donors (controls) and patients with asthma or COPD. Total GAG synthesis was assessed by [ 3 H]-glucosamine incorporation. GAG were isolated, purified, fractionated by electrophoresis and characterised using specific GAG-degrading enzymes. Secretion of hyaluronic acid (HA) by ASMC from patients with asthma or COPD was significantly decreased compared with controls. RT-PCR analysis and western blotting revealed that this decrease was associated with a significant reduction in the expression of HA synthase-1 and -2 and a significant increase of hyaluronidase-1. Furthermore, the expression of the HA receptor CD44 was significantly decreased, whereas the receptor for HA-mediated motility was not expressed in asthma or COPD. Our results indicate that there is a decreased expression of HA in asthma and COPD associated with a synergistic regulation of HA metabolising enzymes that may regulate the pathological airway remodelling in these lung diseases.
The impact of COPD on health status: findings from the BOLD study
Authors: Christer Janson, Guy Marks, Sonia Buist, Louisa Gnatiuc, Thorarinn Gislason, Mary Ann McBurnie, Rune Nielsen, Michael Studnicka, Brett Toelle, Bryndis Benediktsdottir, Peter Burney
Journal: European Respiratory Journal (2013)

The aim of this study was to describe the impact of chronic obstructive pulmonary disease (COPD) on health status in the Burden of Obstructive Lung Disease (BOLD) populations. We conducted a cross-sectional, general population-based survey in 11 985 subjects from 17 countries. We measured spirometric lung function and assessed health status using the Short Form 12 questionnaire. The physical and mental health component scores were calculated. Subjects with COPD (post-bronchodilator forced expiratory volume in 1 s/forced vital capacity &lt;0.70, n = 2269) had lower physical component scores (44±10 <i>versus</i> 48±10 units, p&lt;0.0001) and mental health component scores (51±10 <i>versus</i> 52±10 units, p = 0.005) than subjects without COPD. The effect of reported heart disease, hypertension and diabetes on physical health component scores (-3 to -4 units) was considerably less than the effect of COPD Global Initiative for Chronic Obstructive Lung Disease grade 3 (-8 units) or 4 (-11 units). Dyspnoea was the most important determinant of a low physical and mental health component scores. In addition, lower forced expiratory volume in 1 s, chronic cough, chronic phlegm and the presence of comorbidities were all associated with a lower physical health component score. COPD is associated with poorer health status but the effect is stronger on the physical than the mental aspects of health status. Severe COPD has a greater negative impact on health status than self-reported cardiovascular disease and diabetes.
Focal Adhesion Kinase Promotes the Aggressive Melanoma Phenotype
Authors: Angela R. Hess, Lynne-Marie Postovit, Naira V. Margaryan, Elisabeth A. Seftor, Galen B. Schneider, Richard E.B. Seftor, Brian J. Nickoloff, Mary J.C. Hendrix
Journal: Cancer Research (2005)

Abstract Malignant melanoma continues to remain a significant health threat, with death often occurring as a result of metastasis. The metastatic phenotype typically is characterized by augmented tumor cell invasion and migration in addition to tumor cell plasticity as shown by vasculogenic mimicry. Therefore, understanding the molecular mechanisms that promote an aggressive phenotype is essential to predicting the likelihood of metastasis at a stage when intervention may be possible. This study focuses on the role of focal adhesion kinase (FAK), a cytoplasmic tyrosine kinase important for many cellular processes, including cell survival, invasion, and migration. We found FAK to be phosphorylated on its key tyrosine residues, Tyr397 and Tyr576, in only aggressive uveal and cutaneous melanoma cells, which correlates with their increased invasion, migration, and vasculogenic mimicry plasticity. Additionally, we confirmed the presence of FAK phosphorylated on Tyr397 and Tyr576 in both cutaneous and uveal melanoma tumors in situ. Examination of a functional role for FAK in aggressive melanoma revealed that disruption of FAK-mediated signal transduction pathways, through the expression of FAK-related nonkinase (FRNK), results in a decrease in melanoma cell invasion, migration, and inhibition of vasculogenic mimicry. Moreover, we found that FRNK expression resulted in a down-regulation of Erk1/2 phosphorylation resulting in a decrease in urokinase activity. Collectively, these data suggest a new mechanism involved in promoting the aggressive melanoma phenotype through FAK-mediated signal transduction pathways, thus providing new insights into possible therapeutic intervention strategies.
Five times: coincidence or something more serious? What should a junior doctor have done? You cannot expect people to be heroes Put out the fire or risk an inferno Present system of whistleblowing is unsatisfactory
Authors: M Irving
Journal: BMJ (1998)

# Five times: coincidence or something more serious? {#article-title-2}

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The anonymous article below was sent to us by a doctor outlining the concerns he had about the competence of a surgeon he once worked with when he was a junior doctor. We asked four other doctors what the junior should have done, what they would have done had they been approached by the junior, and what the implications are for the regulation of medicine.

Perioperative mortality (death within 28 days of an operation) has became a key surgical phrase in the past decade, particularly after the publication of the first report of the confidential inquiry into perioperative deaths. This document detailed a variety of surgical and anaesthetic disasters, and, although it pointed out that many perioperative deaths were and remain unavoidable, there were contributory factors such as inadequate hospital facilities, poor supervision of junior doctors, and inappropriate surgery in severely ill patients.

This and subsequent reports, together with regular intradepartmental and interdepartmental audits, have raised the awareness of perioperative mortality. All operative deaths should now be discussed to discover if care could have been improved or death avoided. I have been fortunate to be a surgical trainee in these more enlightened times. Usually, the audits I have attended have had an average of one death every six months from routine general surgery lists (somewhat more from emergency surgery), and even fewer during my five years in specialist training. With one exception: during a six month period on one firm, five patients on routine lists died from a variety of reasons. All of these patients were led to believe that their conditions would be substantially improved if not cured by the surgery, and yet within a matter of days they were dead. I felt at the time that certain questions were overlooked, if not ignored. My polite …