tbuckley/cabot-search huggingface dataset:
NO with no NOS in ischemic heart
Authors: R KUDEJ, C DEPRE
Journal: Cardiovascular Research (2007)

See article by Martin et al.  [5]  (pages 46–55) in this issue. 

The seminal observation by Furchgott and Zawadzki [1] of a paradoxical vasoconstrictive effect of acetylcholine in arteries deprived of endothelium paved the way for the rapid discovery of nitric oxide (NO) and of the mechanisms of NO generation by a specific family of isoforms known as NO synthases (NOS). The role of NO in the endothelium was characterized as a predominant mechanism of vasodilation through the production of cyclic GMP (cGMP) in vascular smooth muscle cells. The rapid progress of this research in endothelial cells automatically led to the question whether the cardiac cell itself could be a source of NO.

It was found that the three characterized isoforms of NOS are expressed in cardiac myocytes [2]. However, the role of NO in the myocardium, and the regulation of its production, seems much more complex than what was described before in the endothelium, and includes both cGMP-dependent and -independent mechanisms. Myocardial NO is involved in cellular processes as diverse as cardiac contractility, Ca2+ handling, mitochondrial respiration, substrate metabolism, generation of radical oxygen species, and ischemic preconditioning among others (see Fig. 1). In addition, the mechanisms of action of NO are diverse and sometimes contradictory. For example, depending on the experimental setting, blocking cardiac NOS can be either beneficial or deleterious for the ischemic heart [3,4]. Part of this complexity comes from the fact that NO production in the heart is performed by the three different isoforms (endothelial, inducible and neuronal) that differ in their properties, … 

*Corresponding author. Tel.: +1 973 972 3926; fax: +1 973 972 7489. Email address: deprech{at}umdnj.edu
Antigen-induced co-capping of IgM and IgD-like receptors on murine B cells.
Authors: J W Goding, J E Layton
Journal: The Journal of Experimental Medicine (1976)

Double fluorescence studies indicated that most mature lymphocytes of 11-52-wk-old mice possess both IgM and IgD-like surface immunoglobulins, while spleen cells from neonatal mice possess surface IgM only. These molecules cap independently with class-specific antisera, but co-cap when capping is induced by antigen. It is proposed that the two heavy chains on individual lymphocytes possess similar or identical antigen-combining sites.
Molecular differences between human and experimental pancreaticobiliary diversion-induced rat pancreatic neoplasia.
Authors: P A Hall, N R Lemoine, G Murphy, R H Dowling
Journal: Gut (1991)

A series of molecular changes are now known to be seen in human pancreatic neoplasia, including the very frequent mutational activation of Kirsten ras oncogene at codon 12, overexpression of the epidermal growth factor receptor, and abnormalities of c-erbB-2 expression. In order to determine whether similar changes can be seen in animal models of pancreatic cancer a molecular analysis of tumours induced in rats by pancreaticobiliary diversion was performed. The polymerase chain reaction was used to amplify portions of the rat Kirsten ras gene and sequence specific oligonucleotide hybridisation was used to define whether sequences were wild type or mutant. No evidence of mutation was found in the Kirsten ras gene at codons 12 or 61, where activating mutations are known to occur. In addition immunohistochemical methods were used to investigate expression of c-erB-2 and the epidermal growth factor receptor but no evidence of abnormal expression was found. We conclude that there are major molecular differences between human and experimental rat pancreatic cancer.
Duplication of Accelerated Evolution and Growth Hormone Gene in Passerine Birds
Authors: Tamaki Yuri, Rebecca T. Kimball, Edward L. Braun, Michael J. Braun
Journal: Molecular Biology and Evolution (2007)

We report the discovery of a duplication of the growth hormone (GH) gene in a major group of birds, the passerines (Aves: Passeriformes). Phylogenetic analysis of 1.3-kb partial DNA sequences of GH genes for 24 species of passerines and numerous outgroups indicates that the duplication occurred in the ancestral lineage of extant passerines. Both duplicates and their open-reading frames are preserved throughout the passerine clade, and both duplicates are expressed in the zebra finch brain, suggesting that both are likely to be functional. The estimated rates of amino acid evolution are more than 10-fold higher in passerine GH genes than in those of their closest nonpasserine relatives. In addition, although the 84 codons sequenced are generally highly conserved for both passerines and nonpasserines, comparisons of the nonsynonymous/synonymous substitution ratios and the rate of predicted amino acid changes indicate that the 2 gene duplicates are evolving under different selective pressures and may be functionally divergent. The evidence of differential selection, coupled with the preservation of both gene copies in all major lineages since the origin of passerines, suggests that the duplication may be of adaptive significance, with possible implications for the explosive diversification of the passerine clade.
The Amsterdam years
Authors: M JANSE
Journal: Cardiovascular Research (2007)

In honour of the fortieth anniversary of Cardiovascular Research , I was approached by the Editorial Team of the Journal to relate some of my experiences as Editor-in-Chief from 1995 to 2002. The following is a collection of memories and observations that may be interesting to editors, reviewers, and authors alike.

The initial months of our editorial term were very hectic. On the one hand this was due to the very short time we had to prepare ourselves, to find a team of associate editors, journal managers, an office, furniture, computers, but, above all a working Manuscript Tracking System. The version we got was brand-new and full of bugs. It behaved like a child who in rapid succession suffered from every known, and unknown, paediatric disease, from mumps to measles. We had adopted many of my predecessor David Hearse's innovations (rapid review, three reviewers, a reward in the form of a compact disk when reviewers met the deadline of 3 weeks, publication of Spotlight Issues devoted to a single topic, etc.) and had received a list of reviewers. Our own innovation was a list of specific keywords, designed by Ruben Coronel and Jan W.T. Fiolet, which was sent to all reviewers, who dutifully returned it. The problems arose when we clicked in the keywords in the Manuscript Tracking System. All of us spent countless evenings and weekends to assign the keywords to the reviewers, and about twice a week the system crashed. All data went down the drain, and the hard disk had to be sent to England. We must have ticked in the keywords of Dr Abd-El Fatah (we did it alphabetically) a dozen times (with Dr Zipes, we … 

m.j.janse{at}amc.uva.nl
Stereotactic radiotherapy for oligometastatic cancer: a prognostic model for survival
Authors: T. de Vin, B. Engels, T. Gevaert, G. Storme, M. De Ridder
Journal: Annals of Oncology (2013)

BackgroundStereotactic radiotherapy (SRT) is a safe and locally effective treatment for patients with inoperable oligometastases. The challenge remains identifying subsets of patients that benefit in terms of overall survival (OS).Patients and methodsBetween 2005 and 2011, 309 patients with ≤5 metastases were treated by stereotactic body radiotherapy (n = 209) and/or by intracranial single or fractionated stereotactic radiotherapy (n = 107). We analyzed OS and carried out a risk factor analysis.ResultsThe median survival of all patients was 24 months. The 3-, 4- and 5-year OS rates were 32%, 25% and 19%, respectively. The following four risk factors were independently associated with impaired OS: nonadenocarcinoma histology (P < 0.01), intracranial metastases (P < 0.01), synchronous oligometastatic disease (P < 0.01) and male gender (P = 0.02). Patients with 0, 1 and 2 risk factors displayed a median survival (95% CI) of 40 (24–63), 29 (23–35) and 23 (16–29) months, respectively, and are defined as patients with good prognosis. Patients with 3 and 4 risk factors had a median survival of 9 (6–11) and 4 (1–7) months only and are defined as bad prognostic patients.ConclusionsWe identified subsets of oligometastatic cancer patients with good prognosis after SRT. These patients are candidates for inclusion in prospective randomized trials for defining the role of SRT in the management of oligometastases.
Inhaled mannitol for non-cystic fibrosis bronchiectasis: Results of a 12 month, multi-centre, double-blind, controlled study
Authors: Diana Bilton, Gregory Tino, Alan Barker, Daniel Chambers, Anthony De Soyza, Lieven Dupont, Conor O'Dochartaigh, Eric van Haren, Luis Otero Vidal, Tobias Welte, Howard Fox, Jian Wu, Brett Charlton
Journal: European Respiratory Journal (2013)

Bronchiectasis, characterised by abnormal bronchial dilatation, is associated with increased sputum production, impaired mucocilliary clearance, mucus accumulation, cough, & recurrent bacterial infection. Inhaled dry powder mannitol (M), an osmotic agent increases mucus clearance acutely & over 24hrs in patients with bronchiectasis, however long term data are needed.   Aim:  The primary study aim was to evaluate the difference in pulmonary exacerbations over 12mths between M & control (C). Secondary endpoints included: Time to first exacerbation, antibiotic use, SGRQ, 24hr sputum volume, Epworth Sleepiness Scale, lung function & safety.   Methods:  A randomised, double-blind, multicentre, phase III study in patients (18-85yr) with a confirmed diagnosis of non-CF bronchiectasis, FEV 1  (40-85% predicted) & ≥ 1.0L. 485 patients (62.7% F), mean age (SD) 59.8 (13.6) were randomised (1:1) to M (400mg bd) or C (50 mg bd). Mean (SD) baseline FEV 1 % was 62.3% (13.5).   Results:  There was a non-significant 8% reduction (Rate ratio 0.92, p=0.31) in the rate of defined pulmonary exacerbations for patients treated with M vs. C. However there was a statistically significant 28% delay in time to first exacerbation (Hazard Ratio: 0.78, p=0.022) & a 24% reduction in days on antibiotics (Rate ratio 0.76, p=0.0496). SGRQ was significantly improved (-2.4, p=0.046).  There was no difference in the number of patients experiencing adverse events (AEs) or serious AEs in the two groups.   Conclusion:  Although the primary endpoint failed to reach significance there are sufficient significant improvements in secondary endpoints to indicate the need for further evaluation of M in bronchiectasis.
AMP-activated protein kinase signaling in metabolic regulation
Authors: Y. C. Long
Journal: Journal of Clinical Investigation (2006)

AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolism. When activated by a deficit in nutrient status, AMPK stimulates glucose uptake and lipid oxidation to produce energy, while turning off energy-consuming processes including glucose and lipid production to restore energy balance. AMPK controls whole-body glucose homeostasis by regulating metabolism in multiple peripheral tissues, such as skeletal muscle, liver, adipose tissues, and pancreatic beta cells--key tissues in the pathogenesis of type 2 diabetes. By responding to diverse hormonal signals including leptin and adiponectin, AMPK serves as an intertissue signal integrator among peripheral tissues, as well as the hypothalamus, in the control of whole-body energy balance.
Nontuberculous mycobacteria in cystic fibrosis associated with allergic bronchopulmonary aspergillosis and steroid therapy
Authors: H. Mussaffi, J. Rivlin, I. Shalit, M. Ephros, H. Blau
Journal: European Respiratory Journal (2005)

Nontuberculous mycobacterial (NTM) infection, particularly due to Mycobacterium abscessus, is an emerging disease that can be relentlessly progressive, particularly in cystic fibrosis (CF) patients. The risk factors that were associated with this increasingly symptomatic infection in a group of CF patients were investigated. A total of 139 CF patients aged 2-52 yrs were reviewed. Sputum was cultured for NTM annually or whenever clinical deterioration was unexplained. In total, 12 patients (8.6%) had positive cultures and six (4.3%) met the criteria for NTM pulmonary disease (five with M. abscessus). Five had allergic bronchopulmonary aspergillosis (ABPA) compared with one out of 133 patients without NTM disease. Five had received systemic steroids (four as a treatment for ABPA) compared with only one out of 133 without NTM lung disease. All six NTM patients deteriorated markedly following mycobacterial infection, and forced expiratory volume in one second dropped 18-46%. Despite prolonged triple antibiotic therapy, M. abscessus was not eradicated, and four out of six did not return to baseline clinically. In conclusion, severe nontuberculous mycobacterial lung disease, particularly with Mycobacterium abscessus, is becoming a perplexing challenge in cystic fibrosis patients. Allergic bronchopulmonary aspergillosis and systemic steroids appear to be risk factors, although small patient numbers limit this to a descriptive observation. When pulmonary condition deteriorates, increased surveillance for mycobacteria would enable prompt diagnosis and treatment.
Acute Modulation of Toll-Like Receptors by Insulin
Authors: Husam Ghanim, Priya Mohanty, Rupali Deopurkar, Ching Ling Sia, Kelly Korzeniewski, Sanaa Abuaysheh, Ajay Chaudhuri, Paresh Dandona
Journal: Diabetes Care (2008)

Low-dose insulin infusion has been shown to exert a prompt and powerful anti-inflammatory effect. Toll-like receptors (TLRs) are major determinants of the inflammatory response to viral and bacterial pathogens. We have now hypothesized that low-dose insulin infusion in obese type 2 diabetic patients suppresses TLR expression.Ten type 2 diabetic patients were infused with a low dose of insulin (2 units/h) and dextrose to maintain normoglycemia for 4 h, while another 14 type 2 diabetic patients were infused with either dextrose or saline for 4 h and served as control subjects. Blood samples were collected before and at 2, 4, and 6 h. TLR expression was determined in mononuclear cells (MNCs).Insulin infusion significantly suppressed TLR1, -2, -4, -7, and -9 mRNA expression in MNCs within 2 h of the infusion, with a maximum fall at 4 h by 24 +/- 9%, 21 +/- 5%, 30 +/- 8%, 28 +/- 5%, and 27 +/- 10% (P < 0.05, for all), respectively, below the baseline. TLR2 protein was suppressed by 19 +/- 7% (P < 0.05) below the baseline at 4 h. The DNA binding of PU.1, a major transcription factor regulating many TLR genes, was concomitantly suppressed by 24 +/- 10% (P < 0.05) by 4 h in MNCs. There was no change in TLR expression or DNA binding by PU.1 following dextrose or saline infusion in the control groups.Insulin suppresses the expression of several TLRs at the transcriptional level, possibly through its suppressive effect on PU.1.
Two Close, Too Close
Authors: Gerald W. Dorn, Luca Scorrano
Journal: Circulation Research (2010)

Mitochondria are key organelles in cell life whose dysfunction is associated with a variety of diseases. Their crucial role in intermediary metabolism and energy conversion makes them a preferred target in tissues, such as the heart, where the energetic demands are very high. In the cardiomyocyte, the spatial organization of mitochondria favors their interaction with the sarcoplasmic reticulum, thereby offering a mechanism for Ca 2+ -mediated crosstalk between these 2 organelles. Recently, the molecular basis for this interaction has begun to be unraveled, and we are learning how endoplasmic reticulum–mitochondrial interactions are often exploited by death signals, such as proapoptotic Bcl-2 family members, to amplify the cell death cascade. Here, we review our present understanding of the structural basis and the functional consequences of the close interaction between sarcoplasmic reticulum and mitochondria on cardiomyocyte function and death.
Neointima formation impairs endothelial muscarinic receptors while enhancing prostacyclin-mediated responses in the rabbit carotid artery.
Authors: G R De Meyer, H Bult, A E Van Hoydonck, F H Jordaens, N Buyssens, A G Herman
Journal: Circulation Research (1991)

The purpose of this study was to determine whether the generation of a neointima, an early step in the development of atherosclerosis, affects endothelium-dependent or -independent vasodilation. The neointima was induced, within 7 days, by positioning a nonocclusive silicone collar around one carotid artery in rabbits. After 1, 2, 7, or 14 days segments were cut from the collar-surrounded region of this artery as well as from the sham-operated contralateral artery and were used for isometric tension recording or for bioassay of nitric oxide (NO). The acetylcholine-induced release of NO was significantly reduced at 7 days. The tension recordings suggested that this already occurred at the earliest stages of neointima formation. Neither the capacity of the endothelial cells to form NO in response to the calcium ionophore A23187 nor the capacity of the underlying smooth muscle cells to relax in response to sources of exogenous NO (3-morpholinosydnonimine and nitroglycerin) was affected by the neointima. Therefore, the impaired endothelium-dependent relaxations to acetylcholine are presumably due to a defect at the level of the endothelial muscarinic receptors. The presence of a fully developed neointima did not alter the responsiveness to isoproterenol and forskolin but enhanced prostacyclin-mediated responses (assessed by iloprost and 13-hydroxyoctadecadienoic acid). These results illustrate selective alterations of endothelial and smooth muscle cell function in intima generation before fatty streak formation.
Ventilation Strategies for Acute Lung Injury and Acute Respiratory Distress Syndrome
Authors: João Batista Borges, Carlos Roberto Ribeiro Carvalho, Marcelo Britto Passos Amato
Journal: JAMA (2008)

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Tachyphylaxis with Amrinone Therapy: Association with Sequestration and Down-Regulation of Lymphocyte Beta-Adrenergic Receptors
Authors: Alan S. Maisel
Journal: Annals of Internal Medicine (1989)

Study Objective: To determine whether intravenous therapy with amrinone changes number, location or function of the β-adrenergic receptors on lymphocytes. Design: Case series. Setting: Veterans hospital coronary care unit. Patients: Eleven patients with decompensated class III or IV heart failure. Interventions: A bolus of intravenous amrinone followed by a continuous infusion at 10 µg/kg · min for 72 hours. Measurements and Main Results: At 24 to 36 hours there was a reduction in pulmonary capillary wedge pressure (35%), right atrial pressure (20%), and systemic vascular resistance (25%) with an increase in cardiac output (30%). By 72 hours all these parameters had returned nearly to baseline levels. This partial cardiovascular tolerance to amrinone was accompanied by a 126% increase in the plasma epinephrine, a 182% increase in norepinephrine, a 31% decrease in the number of β-adrenergic receptors on lymphocytes, and a 36% decrease in isoproterenol-stimulated cyclicadenosine monophosphate on lymphocytes. The number of sequestered receptors doubled during the treatment, and the extent of sequestration correlated well with the extent of receptor down-regulation. Conclusions: The hemodynamic responses to amrinone had virtually returned to baseline by 72 hours. This tolerance was accompanied by increased plasma catecholamines, and a down-regulation, desensitization, and sequestration of β-adrenergic receptors on lymphocytes. We suggest that these receptor changes also occur in cardiovascular tissues and may in part account for the tolerance to amrinone.
Aortitis presenting as mitral stenosis and aortic regurgitation
Authors: D. C. Dunn, S. C. Lennox
Journal: Thorax (1969)

Originally Dr. Rod Elford had planned to pursue a career in sports medicine. An introduction to space medicine and the possibilities inherent in telemedicine changed all that, and last year he became the first Canadian physician to complete a clinical fellowship in this emerging field. Observers think he is likely to be the first of many.
ACC/AHA Clinical Performance Measures for Adults With ST-Elevation and Non–ST-Elevation Myocardial Infarction
Authors: Harlan M. Krumholz, Jeffrey L. Anderson, Neil H. Brooks, Francis M. Fesmire, Costas T. Lambrew, Mary Beth Landrum, W. Douglas Weaver, John Whyte, Robert O. Bonow, Susan J. Bennett, Gregory Burke, Kim A. Eagle, Harlan M. Krumholz, Costas T. Lambrew, Jane Linderbaum, Frederick A. Masoudi, Sharon-Lise T. Normand, Ileana L. PiÑa, Martha J. Radford, John S. Rumsfeld, James L. Ritchie, John A. Spertus
Journal: Journal of the American College of Cardiology (2005)
Chipping away at the common epilepsies with complex genetics: the 15q13.3 microdeletion shows the way
Authors: John C Mulley, Leanne M Dibbens
Journal: Genome Medicine (2009)

The idiopathic epilepsies are genetically heterogeneous with more than 50 clinical classifications. They are characterized by episodic seizures arising from erratic neuronal discharge in susceptible individuals. The most common predisposing genetic cause is the recently discovered chromosome 15q13.3 microdeletion. Other disorders previously attributed to the same lesion include autism, intellectual disability and schizophrenia. This phenotypic spectrum is most easily imagined as a contiguous gene syndrome with idiopathic generalized epilepsy as the most common clinical manifestation. Expressivity of the microdeletion in carriers is too variable for antenatal prediction of phenotype to be possible; however, when it is detected in living affected cases, it can be taken as the major predisposing cause for the observed phenotype. The discovery of this small 15q13.3 lesion barely scratches the surface that conceals what we ultimately need to know about the molecular genetic mechanisms behind the common epilepsies with complex genetics, but it provides valuable insight into how to proceed toward that goal.