tbuckley/cabot-search huggingface dataset:
Expression of skeletal muscle sodium channel (Nav1.4) or connexin32 prevents reperfusion arrhythmias in murine heart
Authors: Evgeny P. Anyukhovsky, Eugene A. Sosunov, Yelena N. Kryukova, Kevin Prestia, Nazira Ozgen, Mathilde Rivaud, Ira S. Cohen, Richard B. Robinson, Michael R. Rosen
Journal: Cardiovascular Research (2010)

Acute myocardial ischaemia induces a decrease in resting membrane potential [which leads to reduction of action potential (AP) Vmax] and intracellular acidification (which closes gap junctions). Both contribute to conduction slowing. We hypothesized that ventricular expression of the skeletal muscle Na+ channel, Nav1.4 (which activates fully at low membrane potentials), or connexin32 (Cx32, which is less pH-sensitive than connexin43) would support conduction and be antiarrhythmic. We tested this hypothesis in a murine model of ischaemia and reperfusion arrhythmias. Empty adenovirus (Sham) or adenoviral constructs expressing either SkM1 (gene encoding Nav1.4) or Cx32 genes were injected into the left ventricular wall. Four days later, ventricular tachycardia (VT) occurred during reperfusion following a 5 min coronary occlusion. In Nav1.4- and Cx32-expressing mice, VT incidence and duration were lower than in Sham (P < 0.05). In vitro multisite microelectrode mapping was performed in the superfused right ventricular wall. To simulate ischaemic conditions, [K+] in solution was increased to 10 mmol/L and/or pH was decreased to 6.0. Western blots revealed Cx32 and Nav1.4 expression in both ventricles. Nav1.4 APs showed higher Vmax and conduction velocity (CV) than Shams at normal and elevated [K+]. Exposure of tissue to acid solution reduced intracellular pH to 6.4. There was no difference in CV between Sham and Cx32 groups in control solution. Acid solution slowed CV in Sham (P < 0.05) but not in Cx32. Nav1.4 or Cx32 expression preserved normal conduction in murine hearts and decreased the incidence of reperfusion VT.
Bridging the efficacy–effectiveness gap: a regulator's perspective on addressing variability of drug response
Authors: Hans-Georg Eichler, Eric Abadie, Alasdair Breckenridge, Bruno Flamion, Lars L. Gustafsson, Hubert Leufkens, Malcolm Rowland, Christian K. Schneider, Brigitte Bloechl-Daum
Journal: Nature Reviews Drug Discovery (2011)
Widespread Recombination in Published Animal mtDNA Sequences1
Authors: A. D. Tsaousis, D. P. Martin, E. D. Ladoukakis, D. Posada, E. Zouros
Journal: Molecular Biology and Evolution (2005)

Mitochondrial DNA (mtDNA) recombination has been observed in several animal species, but there are doubts as to whether it is common or only occurs under special circumstances. Animal mtDNA sequences retrieved from public databases were unambiguously aligned and rigorously tested for evidence of recombination. At least 30 recombination events were detected among 186 alignments examined. Recombinant sequences were found in invertebrates and vertebrates, including primates. It appears that mtDNA recombination may occur regularly in the animal cell but rarely produces new haplotypes because of homoplasmy. Common animal mtDNA recombination would necessitate a reexamination of phylogenetic and biohistorical inference based on the assumption of clonal mtDNA transmission. Recombination may also have an important role in producing and purging mtDNA mutations and thus in mtDNA-based diseases and senescence.
Stent Placement in Patients With Atherosclerotic Renal Artery Stenosis and Impaired Renal Function
Authors: Liesbeth Bax, Arend-Jan J. Woittiez, Hans J. Kouwenberg, Willem P. T. M. Mali, Erik Buskens, Frederik J. A. Beek, Branko Braam, Frans T. M. Huysmans, Leo J. Schultze Kool, Matthieu J. C. M. Rutten, Cornelius J. Doorenbos, Johannes C. N. M. Aarts, Ton J. Rabelink, Pierre-Francois Plouin, Alain Raynaud, Gert A. van Montfrans, Jim A. Reekers, Anton H. van den Meiracker, Peter M. T. Pattynama, Peter J. G. van de Ven, Dammis Vroegindeweij, Abraham A. Kroon, Michiel W. de Haan, Cornelis T. Postma, Jaap J. Beutler
Journal: Annals of Internal Medicine (2009)

Background: Little is known about the efficacy and safety of renal artery stenting in patients with atherosclerotic renal artery stenosis (ARAS) and impaired renal function. Objective: To determine the efficacy and safety of stent placement in patients with ARAS and impaired renal function. Design: Randomized clinical trial. Randomization was centralized and computer generated, and allocation was assigned by e-mail. Patients, providers, and persons who assessed outcomes were not blinded to treatment assignment. Setting: 10 European medical centers. Participants: 140 patients with creatinine clearance less than 80 mL/min per 1.73 m2 and ARAS of 50% or greater. Intervention: Stent placement and medical treatment (64 patients) or medical treatment only (76 patients). Medical treatment consisted of antihypertensive treatment, a statin, and aspirin. Measurements: The primary end point was a 20% or greater decrease in creatinine clearance. Secondary end points included safety and cardiovascular morbidity and mortality. Results: Forty-six of 64 patients assigned to stent placement had the procedure. Ten of the 64 patients (16%) in the stent placement group and 16 patients (22%) in the medication group reached the primary end point (hazard ratio, 0.73 [95% CI, 0.33 to 1.61]). Serious complications occurred in the stent group, including 2 procedure-related deaths (3%), 1 late death secondary to an infected hematoma, and 1 patient who required dialysis secondary to cholesterol embolism. The groups did not differ for other secondary end points. Limitation: Many patients were falsely identified as having renal artery stenosis greater than 50% by noninvasive imaging and did not ultimately require stenting. Conclusion: Stent placement with medical treatment had no clear effect on progression of impaired renal function but led to a small number of significant procedure-related complications. The study findings favor a conservative approach to patients with ARAS, focused on cardiovascular risk factor management and avoiding stenting. Primary Funding Source: Dutch Kidney Foundation, Bayer, Cordis, and Pfizer.
Prospective Study of Mesothelioma Mortality in Turkish Villages With Exposure to Fibrous Zeolite
Authors: Y. Izzettin Baris, Philippe Grandjean
Journal: JNCI Journal of the National Cancer Institute (2006)

Mesothelioma incidence is high in certain villages on the Anatolian plateau in Turkey, where environmental exposure includes erionite, a form of zeolite fibers, from the local volcanic tuff. Previous studies of this exposure were cross-sectional or with a follow-up period of only a few years. A prospective study of residents of two exposed and one nearby control village was initiated in 1979 and continued through December 31, 2003. A total of 891 men and women, aged 20 years or older, were included, 230 of them residing in the village without known exposure to erionite. Mortality data were obtained from hospital records and death certificates. During the 23-year follow-up, 372 deaths occurred; 119 of these were from mesothelioma, which was the cause of 44.5% of all deaths in the exposed villages. Seventeen patients had peritoneal mesothelioma; the rest had pleural mesothelioma. Only two cases of mesothelioma, one of each type, occurred in the control village-both in women born elsewhere. When standardized to the world population, the pleural mesothelioma incidence was approximately 700 and 200 cases per 100,000 people annually in the two exposed villages and about 10 cases per 100,000 people in the control village. When we used Danish data for comparison, the standardized pleural mesothelioma mortality rate was 485 (95% confidence interval = 395 to 590). Our results emphasize the severity of the mesothelioma endemic in erionite-exposed areas of Turkey and call for intensified prevention of mesothelioma by limiting environmental exposures to these fibers.
Principles of Appropriate Antibiotic Use for Treatment of Nonspecific Upper Respiratory Tract Infections in Adults: Background
Authors: Ralph Gonzales, John G. Bartlett, Richard E. Besser, John M. Hickner, Jerome R. Hoffman, Merle A. Sande
Journal: Annals of Internal Medicine (2001)

The following principles of appropriate antibiotic use for adults with nonspecific upper respiratory tract infections apply to immunocompetent adults without complicating comorbid conditions, such as chronic lung or heart disease. 1. The diagnosis of nonspecific upper respiratory tract infection or acute rhinopharyngitis should be used to denote an acute infection that is typically viral in origin and in which sinus, pharyngeal, and lower airway symptoms, although frequently present, are not prominent. 2. Antibiotic treatment of adults with nonspecific upper respiratory tract infection does not enhance illness resolution and is not recommended. Studies specifically testing the impact of antibiotic treatment on complications of nonspecific upper respiratory tract infections have not been performed in adults. Life-threatening complications of upper respiratory tract infection are rare. 3. Purulent secretions from the nares or throat (commonly observed in patients with uncomplicated upper respiratory tract infection) predict neither bacterial infection nor benefit from antibiotic treatment.
Contractile and biochemical responses of cardiac and skeletal muscle to isoproterenol covalently linked to glass beads.
Authors: W R Ingerebretsen, E Becker, W F Friedman, S E Mayer
Journal: Circulation Research (1977)

The effects of (-)-isoproterenol covalently linked to glass beads on inotropic state, cyclic AMP concentration, and phosphorylase b to a conversion was studied in cat and guinea pig papillary muscles. Biochemical responses also were measured in mouse diaphragm sections. In cat papillary muscles under normal conditions and in guinea pig muscles partly depolarized with 22 mM K+ an increased inotropic state and phosphorylase activation could be dissociated from the formation of cyclic AMP. This contrasts with close correlation reported between isometric tension and cyclic AMP concentration in guinea pig papillary muscles exposed to varying concentrations of isoproterenol dissolved in the bath medium. The cyclic nucleotide did increase in guinea pig papillary muscles exposed to a freshly prepared batch of isoproterenol beads and in the mouse diaphragms. The type and age of the bead preparation had marked effects on all responses that were measured and on the rate of leakage of biologically active products from the beads. Nevertheless, experimental conditions could be obtained under which the initiation of the contractile and biochemical responses was probably limited to intense stimulation of receptors at or near the points of contact between beads and muscle and not due to gross leakage into the bath. The results indicate that cyclic AMP is probably involved in the initiation but not the propagation of the inotropic response of papillary muscles exposed to isoproterenol glass beads.
Rhinovirus infection liberates planktonic bacteria from biofilm and increases chemokine responses in cystic fibrosis airway epithelial cells
Authors: S. S. Chattoraj, S. Ganesan, A. M. Jones, J. M. Helm, A. T. Comstock, R. Bright-Thomas, J. J. LiPuma, M. B. Hershenson, U. S. Sajjan
Journal: Thorax (2011)

<h3>Background</h3> Intermittent viral exacerbations in patients with cystic fibrosis (CF) with chronic <i>Pseudomonas aeruginosa</i> (PA) infection are associated with increased bacterial load. A few clinical studies suggest that rhinoviruses (RV) are associated with the majority of viral-related exacerbations in CF and require prolonged intravenous antibiotic treatment. These observations imply that acute RV infection may increase lower respiratory symptoms by increasing planktonic bacterial load. However, the underlying mechanisms are not known. <h3>Methods</h3> Primary CF airway epithelial cells differentiated into mucociliary phenotype were infected with mucoid PA (MPA) followed by RV and examined for bacterial density, biofilm mass, levels of chemokines and hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>). The need for dual oxidase 2, a component of NADPH oxidase, in RV-induced generation of H<sub>2</sub>O<sub>2</sub> in CF cells was assessed using gene-specific siRNA. <h3>Results</h3> Superinfection with RV increased chemokine responses in CF mucociliary-differentiated airway epithelial cells with pre-existing MPA infection in the form of biofilm. This was associated with the presence of planktonic bacteria at both the apical and basolateral epithelial cell surfaces. Further, RV-induced generation of H<sub>2</sub>O<sub>2</sub> via dual oxidase 2 in CF cells was sufficient for dispersal of planktonic bacteria from the biofilm. Inhibition of NADPH oxidase reduced bacterial transmigration across mucociliary-differentiated CF cells and the interleukin-8 response in MPA- and RV-infected cells. <h3>Conclusion</h3> This study shows that acute infection with RV liberates planktonic bacteria from biofilm. Planktonic bacteria, which are more proinflammatory than their biofilm counterparts, stimulate increased chemokine responses in CF airway epithelial cells which, in turn, may contribute to the pathogenesis of CF exacerbations.
BRCA1 and c-Myc Associate to Transcriptionally Repress Psoriasin, a DNA Damage–Inducible Gene
Authors: Richard D. Kennedy, Julia J. Gorski, Jennifer E. Quinn, Gail E. Stewart, Colin R. James, Stephen Moore, Karl Mulligan, Ethan D. Emberley, Tong F. Lioe, Patrick J. Morrison, Paul B. Mullan, George Reid, Patrick G. Johnston, Peter H. Watson, D. Paul Harkin
Journal: Cancer Research (2005)

Abstract Evidence is accumulating to suggest that some of the diverse functions associated with BRCA1 may relate to its ability to transcriptionally regulate key downstream target genes. Here, we identify S100A7 (psoriasin), S100A8, and S100A9, members of the S100A family of calcium-binding proteins, as novel BRCA1-repressed targets. We show that functional BRCA1 is required for repression of these family members and that a BRCA1 disease–associated mutation abrogates BRCA1-mediated repression of psoriasin. Furthermore, we show that BRCA1 and c-Myc form a complex on the psoriasin promoter and that BRCA1-mediated repression of psoriasin is dependent on functional c-Myc. Finally, we show that psoriasin expression is induced by the topoisomerase IIα poison, etoposide, in the absence of functional BRCA1 and increased psoriasin expression enhances cellular sensitivity to this chemotherapeutic agent. Therefore, we identified a novel transcriptional mechanism that is likely to contribute to BRCA1-mediated resistance to etoposide.
Extensive changes in liver gene expression induced by Hereditary Tyrosinemia type I are not normalized by treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC)
Authors: Marjanka C Luijerink, Saskia M.M Jacobs, Ellen A.C.M van Beurden, Leander P Koornneef, Leo W.J Klomp, Ruud Berger, Inge E.T van den Berg
Journal: Journal of Hepatology (2003)
Liver Transplantation for Hepatocellular Carcinoma: An Appraisal of Current Controversies
Authors: Yee Lee Cheah, Pierce K.H Chow
Journal: Liver Cancer (2012)

Cost-effective and efficacious approaches to the management of hepatocellular carcinoma (HCC) must be developed in response to the rising incidence of this disease worldwide. While surgical resection is the current standard of care, most patients afflicted with HCC are unresectable at diagnosis. Developing good therapy for these patients is thus imperative. Liver transplantation offers the possibility of extirpation of not only the tumor but also the remaining cirrhotic liver. Transplantation is hence an ideal treatment option for early HCC patients with poor liver function. When transplantation occurs within the established Milan criteria, the outcomes are good (5-year survival >60%). Current efforts are under way to expand the indications for transplantation beyond the Milan criteria. The resulting surge of new algorithms may potentially shape a new system of transplantation criteria based on personalized parameter calculations. However, this change in criteria is not without controversy, and data remains inconclusive. Current bridging strategies have been similarly hindered by lack of consensus because of the lack of randomized, controlled trials demonstrating their efficacy. In addition, debate continues on the role of transplantation in early (resectable) HCC with good liver function. Issues of reimbursement, the paucity of available donor livers, and governmental funding (or lack thereof) continue to complicate the situation. In this review, issues preventing or facilitating globally consistent treatment strategies for HCC are discussed.
Molecular Alterations in Spontaneous Sputum of Cancer-Free Heavy Smokers: Results from a Large Screening Program
Authors: Ekaterina Baryshnikova, Annarita Destro, Maurizio Valentino Infante, Silvio Cavuto, Umberto Cariboni, Marco Alloisio, Giovanni Luca Ceresoli, Romano Lutman, Giorgio Brambilla, Giuseppe Chiesa, Gianni Ravasi, Massimo Roncalli
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The high mortality rate for lung cancer is likely to be reduced by the development of a panel of sensitive biological markers able to identify early-stage lung cancers or subjects at high risk. The aim of this study was to establish the frequency of K-ras and p53 mutations and p16INK4A, RASSF1A, and NORE1A hypermethylation in sputum of a large cohort of cancer-free heavy smokers and to assess whether these markers are suitable for a routine use in the clinical practice for the early diagnosis of pulmonary cancer. Experimental Design: Sputum samples were collected from 820 heavy smokers. Inclusion criteria consisted of radiologic and cytologic absence of pulmonary lesions, age at least 60 years, male gender, and a smoking history of at least 20 pack-years. Results: The analysis identified 56 individuals (6.9%) with one molecular alteration. p53 mutation and p16INK4A, RASSF1A, and NORE1A methylation frequencies were 1.9%, 5.1%, 0.8%, and 1.0%, respectively; no K-ras mutations were found. One patient with p53 mutations was diagnosed with an early-stage lung cancer after 3-years of follow-up. The molecular analysis of bronchoscopy samples confirmed in half of the cases alterations present in sputum without revealing additional molecular changes. Conclusions: Genetic and epigenetic abnormalities can be detected in cancer-free heavy smokers. Although the predictive value of the cancer risk is still to be established as it requires not less than 5 years of follow-up, p53 and p16INK4A are more promising candidates than K-ras, RASSF1A, and NORE1A for the pulmonary molecular screening of heavy smokers healthy individuals.
Peptide Aptamers Targeting Mutant p53 Induce Apoptosis in Tumor Cells
Authors: Elisa Guida, Andrea Bisso, Cristina Fenollar-Ferrer, Marco Napoli, Claudio Anselmi, Javier E. Girardini, Paolo Carloni, Giannino Del Sal
Journal: Cancer Research (2008)

Mutations in the p53 tumor suppressor gene frequently result in expression of p53 point mutants that accumulate in cancer cells and actively collaborate with tumor progression through the acquisition of novel properties. Interfering with mutant p53 functions may represent a valid alternative for blocking tumor growth and development of aggressive phenotypes. The interactions and activities of selected proteins can be specifically modulated by the binding of peptide aptamers (PA). In the present work, we isolated PAs able to interact more efficiently with p53 conformational mutants compared with wild-type p53. The interaction between mutant p53 and PAs was further characterized using molecular modeling. Transient expression of PAs was able to reduce the transactivation activity of mutant p53 and to induce apoptosis specifically in cells expressing mutant p53. These PAs could provide a potential strategy to inhibit the oncogenic functions of mutant p53 and improve mutant p53-targeted cancer therapies.
Where does fast and frugal cognition stop? The boundary between complex cognition and simple heuristics
Authors: Thom Baguley, S. Ian Robertson
Journal: Behavioral and Brain Sciences (2000)

Simple heuristics that make us smart presents a valuable and valid interpretation of how we make fast decisions particularly in situations of ignorance and uncertainty. What is missing is how this intersects with thinking under even greater uncertainty or ignorance, such as novice problem solving, and with the development of expert cognition.
Involvement of nitric oxide system in experimental muscle crush injury.
Authors: I Rubinstein, Z Abassi, R Coleman, F Milman, J Winaver, O S Better
Journal: Journal of Clinical Investigation (1998)

Muscle crush injury is often complicated by hemodynamic shock, electrolyte disorders, and myoglobinuric renal failure. In this study, we examined the involvement of the nitric oxide (NO) system in the development of muscle damage in an experimental model of crush injury induced by exertion of standardized mechanical pressure on tibialis muscle of rat. The intact limb served as a control. Four days after injury, the crushed muscle was characterized by extreme capillary vasodilatation as demonstrated by histological morphometric analysis. These changes were accompanied by muscle hyperperfusion as evaluated by measurements of femoral blood flow (ultrasonic flowmetry) and capillary blood flow (laser-doppler flowmetry). Treatment with Nomega-nitro-L-arginine methyl ester, a NO synthase (NOS) inhibitor, largely decreased the hyperperfusion. Furthermore, the expression of the different NOS isoforms, assessed by reverse transcription-PCR and immunoreactive levels, determined by Western blot, revealed a remarkable induction of the inducible NOS in the crushed limb. Similarly, endothelial NOS mRNA increased gradually after the induction of muscle damage. In contrast, the major muscular NOS, i.e., neuronal isoform remained unchanged. In line with the alterations in the mRNA levels, Western blot analysis revealed parallel changes in the immunoreactive levels of the various NOS. These findings indicate that muscle crush is associated with activation of the NO system mainly due to enhancement of iNOS. This may contribute to NO-dependent extreme vasodilatation in the injured muscle and aggravate the hypovolemic shock after crush injury.
The treatment of cutaneous telangiectasia with the argon laser
Authors: Julia A. Newton, D.H. McGibbon
Journal: British Journal of Dermatology (1985)

The argon laser is of considerable value in the treatment of port wine stains. It is also a useful tool for the treatment of other vascular anomalies. We report our experience with 31 patients. A variety of lesions were treated: post-radiation telangiectasia (2 patients); adenoma sebaceum (1); spider naevi (II); post rosacea telangiectasia of the nose (3); arborizing telangiectasia of the legs (4); venous flares of the legs (5); angiokeratoma of the thigh (1); and a miscellaneous group (4). The patients have been followed up for between 6 and 24 months. Good results were obtained in patients with spider naevi and arborizing telangiectasia of the legs. Satisfactory results were seen in patients with post rosacea nasal telangiectasia, angiokeratoma of the thigh and in post-radiation telangiectasia. The argon laser was found not to be useful in the majority of patients with venous flares of the legs. Hypopigmentation and mild skin atrophy was seen as a result of the laser treatment in four patients only. In none of the patients was there appreciable scarring.