tbuckley/cabot-search huggingface dataset:
Macrophage Metalloelastase Mediates Acute Cigarette Smoke–induced Inflammation via Tumor Necrosis Factor-α Release
Authors: Andrew Churg, Rong D. Wang, Hsin Tai, Xiaoshan Wang, Changshi Xie, Jin Dai, Steven D. Shapiro, Joanne L. Wright
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

The cells and proteases that mediate cigarette smoke–induced emphysema are controversial, with evidence favoring either neutrophils and neutrophil-derived serine proteases or macrophages and macrophage-derived metalloproteases as the important effectors. We recently reported that both macrophage metalloelastase (MMP-12) and neutrophils are required for acute cigarette smoke-induced connective tissue breakdown, the precursor of emphysema. Here we show how these disparate observations can be linked. Both wild-type (MMP-12 +/+) mice and mice lacking MMP-12 (MMP-12 −/−) demonstrated rapid increases in whole-lung nuclear factor-κB activation and gene expression of proinflammatory cytokines after cigarette smoke exposure, indicating that a lack of MMP-12 does not produce a global failure to upregulate inflammatory mediators. However, only MMP-12 +/+ mice demonstrated increased whole-lung tumor necrosis factor-α (TNF-α) protein or release of TNF-α from cultured alveolar macrophages exposed to smoke in vitro. Levels of whole-lung E-selectin, an endothelial activation marker, were increased in only MMP-12 +/+ mice. These findings suggest that, acutely, MMP-12 mediates smoke-induced inflammation by releasing TNF-α from macrophages, with subsequent endothelial activation, neutrophil influx, and proteolytic matrix breakdown caused by neutrophil-derived proteases. TNF-α release may be a general mechanism whereby metalloproteases drive cigarette smoke–induced inflammation.
The wavelength of the cardiac impulse and reentrant arrhythmias in isolated rabbit atrium. The role of heart rate, autonomic transmitters, temperature, and potassium.
Authors: J L Smeets, M A Allessie, W J Lammers, F I Bonke, J Hollen
Journal: Circulation Research (1986)

We measured the wavelength of the cardiac impulse, defined as the distance traveled by the depolarization wave during the functional refractory period, in isolated narrow strips of rabbit atrium. During control, wavelength was 42 mm during pacing with 2 Hz, and was 28 mm at the maximum pacing rate; early premature beats had a wavelength as short as 23 mm. Administration of carbamylcholine (4 X 10(-7) g/ml) shortened the wavelength to 21 mm during 2 Hz, 18 mm at the maximum pacing rate Fmax, and 16 mm during an early premature impulse, respectively. The effects of epinephrine (6 X 10(-7) M) were strongly rate dependent. At slow heart rates, epinephrine clearly prolonged the wavelength (58 mm), whereas, during maximum pacing, wavelength remained unchanged (28 mm). Hypokalemia (2 mM) decreased the length of the impulse at all stimulation frequencies. Moderate hyperkalemia (5.6 and 7.0 mM) did not modify wavelength because refractoriness and conduction velocity were affected proportionally. Above 7.0 mM potassium, the wavelength became progressively prolonged because of the development of post-repolarization refractoriness. Cooling to 27 degrees C resulted in a slight lengthening of the impulse. At lower temperatures, however, wavelength prolonged significantly because of a relatively strong prolongation of the refractory period. In separate experiments in 15 X 20 mm segments of atrium, reentrant tachyarrhythmias were induced and the circuit size compared with the wavelength. The size of intraatrial circuits was similar to the magnitude of the measured wavelength during maximum pacing. Carbamylcholine and hypokalemia, both of which shorten the impulse length, also clearly decreased the size of reentrant circuits. Cooling to 27 degrees C, which affects both refractoriness and conduction velocity, only slightly prolonged the wavelength; accordingly, the size of reentrant circuits at 27 degrees C was only slightly longer than at 37 degrees C. These experiments emphasize the importance of the wavelength of the cardiac impulse in relation to the occurrence of intramyocardial reentry.
NHS will see more doctors retiring early and working abroad as result of squeeze, BMA head says
Authors: A. O'Dowd
Journal: BMJ (2010)

Three leading NHS unions have questioned the wisdom of the government’s obligatory £15bn-20bn efficiency savings, saying a review of NHS resources would better identify where savings could be made.

The BMA, Royal College of Nursing, and Unison, all giving evidence to the parliamentary health select committee, said there were other ways the NHS could save money rather than the government’s insistence that the whole NHS make £15bn-20bn (€17bn-23bn; $24bn-32bn) worth of efficiency savings by 2014.

MPs on the committee, as part of their ongoing inquiry into public expenditure, asked the witnesses what impact the efficiency savings would have over the next few years given October’s comprehensive spending …
Left Atrial Appendage Occlusion Eliminates the Need for Warfarin
Authors: David R. Holmes, Robert S. Schwartz
Journal: Circulation (2009)

is the third leading cause of mortality and is a leading cause of disability in the world today.Current estimates suggest a stroke incidence of 780 000 cases yearly, and it remains the most feared complication of cardiovascular disease. 1 Brain ischemia is multifactorial-it may result from carotid artery occlusion, plaque embolization, and aortic atheromatous debris.A major cause is cardiac emboli, most commonly occurring in patients with atrial fibrillation.This association is assuming increased importance as atrial fibrillation markedly increases with the aging population. Emboli in Atrial Fibrillation: The Left Atrial AppendageThrombogenesis in atrial fibrillation has generated considerable interest, beginning with Virchow, who proposed a set of criteria needed for thrombus formation.All 3 elements of Virchow Triad typically exist in the atrial fibrillation setting-structural and vessel wall abnormalities, abnormal blood flow patterns, and abnormal constituents in blood,The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.
Unexpected Cardiac Arrest During Anesthesia and Surgery
Authors: Gordon Taylor
Journal: JAMA (1976)

Medical and legal records of 41 cases of cardiac arrest that occurred during surgery were supplied by a professional liability insurance company and a review was undertaken in an attempt to identify recurring or common factors. The majority of patients in this study were healthy and required relatively routine elective surgical procedures. Only three of the patients survived the cardiac arrest and returned to normal activities. The remaining patients either died in the hospital or had a major central nervous system deficit. Hypoxia from hypoventilation and low levels of inspired oxygen appeared to be the chief cause of cardiac arrest in this study. Because of the unknown frequency of cardiac arrest during surgery, we recommend the establishment of a national registry of cardiac arrest cases that occur in surgical patients, in order to monitor incidence, causes, and outcome. Only in this way will it be possible to lessen the frequency of this disastrous event. (<i>JAMA</i>236:2758-2760, 1976)
Transcriptional changes associated with breast cancer occur as normal human mammary epithelial cells overcome senescence barriers and become immortalized
Authors: Yizheng Li, Jing Pan, Jian-Liang Li, Jee Hyung Lee, Chris Tunkey, Katie Saraf, James C Garbe, Maryann Z Whitley, Scott A Jelinsky, Martha R Stampfer, Steven A Haney
Journal: Molecular Cancer (2007)

Abstract Background Human mammary epithelial cells (HMEC) overcome two well-characterized genetic and epigenetic barriers as they progress from primary cells to fully immortalized cell lines in vitro . Finite lifespan HMEC overcome an Rb-mediated stress-associated senescence barrier (stasis), and a stringent, telomere-length dependent, barrier (agonescence or crisis, depending on p53 status). HMEC that have overcome the second senescence barrier are immortalized. Methods We have characterized pre-stasis, post-selection (post-stasis, with p16 silenced), and fully immortalized HMEC by transcription profiling and RT-PCR. Four pre-stasis and seven post-selection HMEC samples, along with 10 representatives of fully immortalized breast epithelial cell lines, were profiled using Affymetrix U133A/B chips and compared using both supervised and unsupervised clustering. Datasets were validated by RT-PCR for a select set of genes. Quantitative immunofluorescence was used to assess changes in transcriptional regulators associated with the gene expression changes. Results The most dramatic and uniform changes we observed were in a set of about 30 genes that are characterized as a "cancer proliferation cluster," which includes genes expressed during mitosis ( CDC2 , CDC25 , MCM2 , PLK1 ) and following DNA damage. The increased expression of these genes was particularly concordant in the fully immortalized lines. Additional changes were observed in IFN-regulated genes in some post-selection and fully immortalized cultures. Nuclear localization was observed for several transcriptional regulators associated with expression of these genes in post-selection and immortalized HMEC, including Rb, Myc, BRCA1, HDAC3 and SP1. Conclusion Gene expression profiles and cytological changes in related transcriptional regulators indicate that immortalized HMEC resemble non-invasive breast cancers, such as ductal and lobular carcinomas in situ , and are strikingly distinct from finite-lifespan HMEC, particularly with regard to genes involved in proliferation, cell cycle regulation, chromosome structure and the DNA damage response. The comparison of HMEC profiles with lines harboring oncogenic changes (e.g. overexpression of Her-2 neu , loss of p53 expression) identifies genes involved in tissue remodeling as well as proinflamatory cytokines and S100 proteins. Studies on carcinogenesis using immortalized cell lines as starting points or "normal" controls need to account for the significant pre-existing genetic and epigenetic changes inherent in such lines before results can be broadly interpreted.
Regional Desensitization of β-Adrenergic Receptor Signaling in Swine With Chronic Hibernating Myocardium
Authors: Vijay S. Iyer, John M. Canty
Journal: Circulation Research (2005)

Contractile reserve during submaximal beta-adrenergic stimulation is attenuated in patients and swine with hibernating myocardium. We tested the hypothesis that this arises as a regional adaptive response in beta-adrenergic adenylyl cyclase coupling. Pigs (n=8) were studied 3 months after instrumentation with a left anterior descending artery (LAD) stenosis when flow (LAD, 0.7+/-0.2 versus 1.2+/-0.1 mL/min per gram in normal remote; P<0.05) and wall thickening (LAD, 15.5 [corrected]+/-3.2% versus 40.0+/-5.5% in remote; P<0.05) were reduced in the absence of infarction. Whereas basal cAMP production was normal (LAD, 87+/-18 versus 91+/-19 pmol/mg per minute; P=NS), responses to isoproterenol were blunted (LAD, 83+/-6 versus 146+/-25 pmol/mg per minute in remote; P<0.05). beta-receptor density and subtype were unchanged, but there was a reduction in the number of high-affinity binding sites (LAD, 40+/-4% versus 53+/-7% in normal remote; P<0.05). The Gialpha2/Gsalpha ratio increased (LAD, 1.8+/-0.3 versus 0.99+/-0.3 in remote myocardium; P<0.05), although GppNHp-stimulated cAMP production was equivocally reduced. Forskolin responses were unchanged and similar to shams. These data indicate regional attenuation of beta-receptor adenylyl cyclase signaling in hibernating myocardium. This blunts the local contractile response to beta-adrenergic stimulation and may serve to protect against a myocardial supply/demand imbalance when external determinants of myocardial workload increase during sympathetic activation.
Stretch-induced Ca2+ signalling in vascular smooth muscle cells depends on Ca2+ store segregation
Authors: Guillaume Gilbert, Thomas Ducret, Roger Marthan, Jean-Pierre Savineau, Jean-François Quignard
Journal: Cardiovascular Research (2014)

AimCalcium is a key second messenger that can be mobilized from both the extracellular medium and intracellular calcium stores. Pulmonary arterial smooth muscle cells (PASMCs) respond to stretch by a calcium increase, a mechanism enhanced during pulmonary hypertension (PH). We investigated the role of the spatial organization between plasma membrane stretch-activated channels (SACs) and intracellular calcium stores [sarcoplasmic reticulum (SR), mitochondria, and lysosomes) in response to stretch.
Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease
Authors: Romina Lomonaco, Carolina Ortiz-Lopez, Beverly Orsak, Amy Webb, Jean Hardies, Celia Darland, Joan Finch, Amalia Gastaldelli, Stephen Harrison, Fermin Tio, Kenneth Cusi
Journal: Hepatology (2011)

The role of adipose tissue insulin resistance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) remains unclear. To evaluate this, we measured in 207 patients with NAFLD (age = 51 ± 1, body mass index = 34.1 ± 0.3 kg/m(2) ) and 22 controls without NAFLD (no NAFLD) adipose tissue insulin resistance by means of a validated index (Adipo-IR(i) = plasma free fatty acids [FFA] x insulin [FPI] concentration) and as the suppression of plasma FFA during an oral glucose tolerance test and by a low-dose insulin infusion. We also explored the relationship between adipose tissue insulin resistance with metabolic and histological parameters by dividing them based on quartiles of adipose tissue insulin resistance (Adipo-IR(i) quartiles: Q1 = more sensitive; Q4 = more insulin resistant). Hepatic insulin resistance, measured as an index derived from endogenous glucose production x FPI (HIRi), and muscle insulin sensitivity, were assessed during a euglycemic insulin clamp with 3-[(3) H] glucose. Liver fat was measured by magnetic resonance imaging and spectroscopy, and a liver biopsy was performed to assess liver histology. Compared to patients without steatosis, patients with NAFLD were insulin resistant at the level of adipose tissue, liver, and skeletal muscle and had higher plasma aspartate aminotransferase and alanine aminotransferase, triglycerides, and lower high-density lipoprotein cholesterol and adiponectin levels (all P < 0.01). Metabolic parameters, hepatic insulin resistance, and liver fibrosis (but not necroinflammation) deteriorated as quartiles of adipose tissue insulin resistance worsened (all P < 0.01).Adipose tissue insulin resistance plays a key role in the development of metabolic and histological abnormalities of obese patients with NAFLD. Treatment strategies targeting adipose tissue insulin resistance (e.g., weight loss and thiazolidinediones) may be of value in this population.
A mechanism responsible for the induction of H-2 restricted second order suppressor T cells.
Authors: I Aoki, M Minami, M E Dorf
Journal: The Journal of Experimental Medicine (1983)

The mechanism by which I-J restrictions were imposed on second-order suppressor cells (Ts2) was analyzed. The induction of Ts2 cells requires presentation of an inducer suppressor factor by a specialized population of factor-presenting cells. The I-J phenotype of this factor-presenting population controls the H-2 restriction of the Ts2 cells. The splenic cells responsible for presenting inducer factor appear to be of macrophage or dendritic cell lineage. Several homologies exist between the mechanism responsible for the induction of H-2-restricted suppressor and helper T cells. Thus, the I region products on specialized presenting cells determine the specificity and genetic restrictions of the T cell. In an H-2 heterozygous F1 animal, two distinct populations of cells can be induced, one specific for each parental H-2 heplotype. Furthermore, the data suggest that the suppressor cells also bear receptors for self H-2 products. The ramifications of these observations for the suppressor cell cascade are discussed.
THE EFFECT OF THE VIRUS: HOST CELL RELATIONSHIP ON INFECTION WITH VACCINIA
Authors: Douglas H. Sprunt
Journal: The Journal of Experimental Medicine (1941)

Experiments are described in which it is shown that, in addition to the amount of virus injected, the chance of a lesion also depends on the tissue mass (number of cells) exposed to the virus shortly after injection, and that the larger the number of host cells per virus particle the greater the probability of a lesion. This point has been shown by three types of experiments: (1) varying the size of the inoculum showed that the smaller sizes were relatively more effective than the larger ones; (2) localizing the virus by the estrogenic hormone decreased the chance of a lesion occurring; (3) spreading the virus over a larger area increased the probability of a lesion. It is also shown that because the ratio of virus particles to host cells varies and because this ratio partly determines whether a lesion occurs, the number of particles of virus cannot be predicted by the use of the Poisson law of small numbers.
Clinical and Genetic Characteristics of Patients With Type 1 Diabetes Associated With Interferon Therapy
Authors: Koji Nakanishi, Satoshi Saitoh
Journal: Diabetes Care (2011)

This study clarified characteristics of interferon-associated type 1 diabetes.The study compared 12 patients with interferon-associated type 1 diabetes with 128 patients with type 1A diabetes with respect to clinical characteristics, and with 10 patients without diabetes despite interferon therapy and 136 normal controls with respect to HLA allele distributions.Patients with interferon-associated type 1 diabetes retained higher levels of fasting serum C peptide as well as GAD65 antibodies than those with type 1A diabetes until 2 to 4 years after onset. HLA-A*2402 was increased among patients with interferon-associated type 1 diabetes compared with those without diabetes, despite interferon therapy (odds ratio [OR] 4.00 [95% CI 1.09-17.26]). The haplotype of DRB1*1302-DQA1*0102-DQB1*0604 was increased in these two groups combined compared with normal controls (OR 5.64 [95% CI 2.67-11.81]).Interferon-associated type 1 diabetes is characterized clinically by high titers of GAD65 antibodies and preserved β-cell function, and genetically by addition of HLA-A*2402to DRB1*1302-DQA1*0102-DQB1*0604.
Sex-Chromosome Homomorphy in Palearctic Tree Frogs Results from Both Turnovers and X–Y Recombination
Authors: Christophe Dufresnes, Amaël Borzée, Agnès Horn, Matthias Stöck, Massimo Ostini, Roberto Sermier, Jérôme Wassef, Spartak N. Litvinchuck, Tiffany A. Kosch, Bruce Waldman, Yikweon Jang, Alan Brelsford, Nicolas Perrin
Journal: Molecular Biology and Evolution (2015)

Contrasting with birds and mammals, poikilothermic vertebrates often have homomorphic sex chromosomes, possibly resulting from high rates of sex-chromosome turnovers and/or occasional X–Y recombination. Strong support for the latter mechanism was provided by four species of European tree frogs, which inherited from a common ancestor (∼5 Ma) the same pair of homomorphic sex chromosomes (linkage group 1, LG1), harboring the candidate sex-determining gene Dmrt1. Here, we test sex linkage of LG1 across six additional species of the Eurasian Hyla radiation with divergence times ranging from 6 to 40 Ma. LG1 turns out to be sex linked in six of nine resolved cases. Mapping the patterns of sex linkage to the Hyla phylogeny reveals several transitions in sex-determination systems within the last 10 My, including one switch in heterogamety. Phylogenetic trees of DNA sequences along LG1 are consistent with occasional X–Y recombination in all species where LG1 is sex linked. These patterns argue against one of the main potential causes for turnovers, namely the accumulation of deleterious mutations on nonrecombining chromosomes. Sibship analyses show that LG1 recombination is strongly reduced in males from most species investigated, including some in which it is autosomal. Intrinsically low male recombination might facilitate the evolution of male heterogamety, and the presence of important genes from the sex-determination cascade might predispose LG1 to become a sex chromosome.
Pseudomonas serology: confusion, controversy, and challenges
Authors: P M Farrell
Journal: Thorax (2006)

Contrasting messages on the diagnostic value of Pseudomonas serology in CF

The two interesting but contrasting (and possibly confusing) papers on Pseudomonas serology in cystic fibrosis (CF) published in this issue of Thorax illustrate the controversy and challenge that have become increasingly important as very young patients are routinely diagnosed through newborn screening. Fortunately, such infants at diagnosis are typically free of Pseudomonas aeruginosa (PA) infection,1 unlike about 30% of those diagnosed by traditional methods following signs/symptoms of CF.2 The potential to eradicate non-mucoid PA, and even to delay transformation to mucoid species,1 makes ascertainment of the initial PA infection one of the highest priorities in current clinical management. Yet, just as in the diagnosis of CF per se, traditional methods of PA identification (relying on microbiology) leave much to be desired in young children with CF. Thus, more attention has focused once again on the potential diagnostic value of Pseudomonas serology. In a recent review Rosenfeld et al 3 stated that “limitations of serologic markers of P aeruginosa infection include lack of commercially available standardized assays and lack of specificity to the site of P aeruginosa infection (i.e. upper or lower airway)”.

The pioneering studies on Pseudomonas serology were published 2–3 decades ago when the research teams of Niels Hoiby and Gerd Doring developed the initial methodology and applied Pseudomonas antibody titre determinations to patients with CF.4–6 The first tests were based on detection of “precipitating antibodies” (precipitins) against a pool of sonicated extracts from common 0-antigen serotypes. Their evaluations showed that rising antibody titres correlated with PA respiratory infections. They also showed6 that, soon after the onset of PA lung infections, the numbers of individual precipitin bands rose and eventually became a sign of “poor prognosis”. Subsequently, Brett and co-workers7 published important …