tbuckley/cabot-search huggingface dataset:
Supernormal excitability as a mechanism of chaotic dynamics of activation in cardiac Purkinje fibers.
Authors: D R Chialvo, D C Michaels, J Jalife
Journal: Circulation Research (1990)

Supernormality, which can be defined as greater than normal excitability during or immediately after action potential repolarization, has been observed in a variety of cardiac preparations. However, as yet, no description of the dynamics of tissue response to repetitive stimulation in the presence of supernormal or relatively supernormal excitability has appeared. Isolated sheep cardiac Purkinje fibers (2-5 mm in length) were superfused with Tyrode's solution and stimulated with depolarizing current pulses through a suction pipette. Recovery of excitability, restitution of the action potential duration, and response patterns were measured in each fiber for a wide range of current amplitudes and stimulation frequencies. When the potassium chloride concentration of the Tyrode's solution was decreased from 7 to 4 mM, the excitability recovery function consistently changed from monophasic ("normal") to triphasic ("supernormal'). During repetitive stimulation at increasing rates, normal preparations responded only with gradual changes in the activation ratio, expressed as periodic phase-locked responses (i.e., Wenckebach-like patterns, etc.). Supernormal preparations showed a nonmonotonic change in the activation ratio, as well as complex aperiodic response patterns. Numerical results from an analytical model gave a quantitative basis for the relation between nonmonotonicity in the excitability function and the development of complex rhythms in cardiac Purkinje fibers. Both our experimental and theoretical results indicate that the presence of supernormality and the slope of the action potential duration restitution curve at short diastolic intervals are responsible for the development of chaotic dynamics. Moreover, our results give an accurate description of the supernormality phenomenon, predict the behavior expected under such conditions, and provide insight about the role of membrane recovery in determining regular and irregular frequency-dependent rhythm and conduction disturbances.
Authors' response: exposing children to secondhand smoke
Authors: John Britton, Jo Leonardi-Bee
Journal: Thorax (2012)

response: exposing children to secondhand smokePool and colleagues make an important point about exposure to tobacco smoke 1 but we are uncertain of the relevance to our paper, 2 which reported the effects of smoking by parents as a behaviour rather than source of passive exposure.While we cannot discount the possibility that children of smokers are more likely to become smokers as a consequence of passive smoke exposure, our interpretation is that it is the behaviour that is responsible.
Recent Strong Positive Selection on Drosophila melanogaster HDAC6, a Gene Encoding a Stress Surveillance Factor, as Revealed by Population Genomic Analysis
Authors: N. Svetec, P. Pavlidis, W. Stephan
Journal: Molecular Biology and Evolution (2009)

Based on nearly complete genome sequences from a variety of organisms, data on naturally occurring genetic variation on the scale of hundreds of loci to entire genomes have been collected in recent years. In parallel, new statistical approaches (such as the composite likelihood ratio and "SweepFinder" tests) have been developed to infer evidence of recent positive selection from these data and to localize the target of selection. Here, we apply these methods to the X chromosome of Drosophila melanogaster in an effort to map genes involved in ecological adaptation. Using slight modifications of these tests that increase their robustness against past demographic changes, we detected evidence that recent strongly positive selection has been acting on a 2.7-kb region in an ancestral African population. This region overlaps with the 3′ end of HDAC6, a gene that encodes a newly characterized stress surveillance factor. HDAC6 is an unusual histone deacetylase being localized in the cytoplasm. Its ubiquitin-binding and tubulin-deacetylase activities suggest that HDAC6 is very different from other histone deacetylases. Indeed, recent discoveries have shown that HDAC6 is a key regulator of cytotoxic stress resistance.
Direct and indirect effects of calcium entry blocking agents on isovolumic left ventricular relaxation in conscious dogs.
Authors: R A Walsh, R A O'Rourke
Journal: Journal of Clinical Investigation (1985)

To assess the direct and indirect effects of the commonly used calcium entry blockers (CEB) upon the major determinants of isovolumic left ventricular relaxation, we administered equidepressant intracoronary (IC, n = 7) and equihypotensive intravenous (n = 12) dosages of diltiazem (16 +/- 3 SE micrograms/kg IC and 63 +/- 9 micrograms/kg i.v.), verapamil (10 +/- 2 and 57 +/- 5 micrograms/kg), and nifedipine (1 +/- 0.1 and 8 +/- 0.3 micrograms/kg) to preinstrumented awake dogs with normal ventricular function. The time constant of left ventricle (LV) relaxation, analyzed by two methods (T1, from the linear relation of the natural logarithm of LV pressure and time; T2, from the linear relation of LV pressure and negative high fidelity LV pressure), was significantly and equivalently prolonged by IC diltiazem (T1 + 48%, P less than 0.02), verapamil (T1 + 43%, P less than 0.001), and nifedipine (T1 + 30%, P less than 0.03). Lesser amounts of each CEB that did not affect rate of LV pressure development or extent of shortening produced no change in T1 or T2. By contrast, intravenous calcium entry blockade either produced no significant change (diltiazem and verapamil) or shortened (nifedipine T1 - 18%, P less than 0.01) LV isovolumic relaxation. However, after beta adrenergic blockade with propranolol (2 mg/kg i.v., n = 6) no change in ventricular relaxation was observed during nifedipine and the time constant was significantly prolonged by verapamil (T1 + 15%, P less than 0.05). We conclude that calcium entry blockade directly impairs normal left ventricular relaxation: This effect is closely linked to the negative inotropic properties of these drugs. The prolongation of isovolumic relaxation produced by calcium blockade is attenuated or even reversed by reflex sympathetic stimulation and favorably altered loading conditions during systemic administration.
Hypoxia-Mediated Induction of the Polyamine System Provides Opportunities for Tumor Growth Inhibition by Combined Targeting of Vascular Endothelial Growth Factor and Ornithine Decarboxylase
Authors: Katrin J. Svensson, Johanna E. Welch, Paulina Kucharzewska, Per Bengtson, Maria Bjurberg, Sven Påhlman, Gerdy B. Ten Dam, Lo Persson, Mattias Belting
Journal: Cancer Research (2008)

Abstract Hypoxia is a hallmark of solid tumors, which may offer opportunities for targeted therapies of cancer; however, the mechanisms that link hypoxia to malignant transformation and tumor progression are not fully understood. Here, we show that up-regulation of the polyamine system promotes cancer cell survival during hypoxic stress. Hypoxia was found to induce polyamine transport and the key enzyme of polyamine biosynthesis, ornithine decarboxylase (ODC), in a variety of cancer cell lines. Increased ODC protein expression was shown in hypoxic, GLUT-1–expressing regions of tumor spheroids and experimental tumors, as well as in clinical tumor specimens. Hypoxic induction of the polyamine system was dependent on antizyme inhibitor (i.e., a key positive regulator of ODC and polyamine transport), as shown by RNA interference experiments. Interestingly, depletion of the polyamines during hypoxia resulted in increased apoptosis, which indicates an essential role of the polyamines in cancer cell adaptation to hypoxic stress. These results were supported by experiments in an in vivo glioma tumor model, showing significantly enhanced antitumor effects of the antiangiogenic, humanized anti–vascular endothelial growth factor (VEGF) antibody bevacizumab when used in combination with the well-established, irreversible inhibitor of ODC, α-difluoromethylornithine. Our results provide important insights into the hypoxic stress response in malignant cells and implicate combined targeting of VEGF and ODC as an alternative strategy to treat cancer disease. [Cancer Res 2008;68(22):9291–301]
Nutrient Metal Sequestration by Calprotectin Inhibits Bacterial Superoxide Defense, Enhancing Neutrophil Killing of Staphylococcus aureus
Authors: Thomas E. Kehl-Fie, Seth Chitayat, M. Indriati Hood, Steven Damo, Nicole Restrepo, Carlos Garcia, Kim A. Munro, Walter J. Chazin, Eric P. Skaar
Journal: Cell Host & Microbe (2011)
Effect of lung transplantation on diaphragmatic function in patients with chronic obstructive pulmonary disease.
Authors: T Wanke, M Merkle, D Formanek, U Zifko, G Wieselthaler, H Zwick, W Klepetko, O C Burghuber
Journal: Thorax (1994)

BACKGROUND--To date there are no data on the effects of lung transplantation on diaphragmatic function in patients with end stage chronic obstructive pulmonary disease (COPD). It is not known whether the relation between the transdiaphragmatic pressure (PDI) and lung volume is altered in recipients after transplantation as a result of changes in diaphragmatic structure caused by chronic hyperinflation. The effect of lung transplantation on diaphragmatic strength was determined in patients with COPD and the relation between postoperative PDI and lung volume analysed. METHODS--Diaphragmatic strength was assessed in eight double lung transplant recipients, six single lung transplant recipients, and in 14 patients with COPD whose lung function was similar to those of the transplant recipients preoperatively. PDI obtained during unilateral and bilateral phrenic nerve stimulation at 1 Hz (twitch PDI) at functional residual capacity (FRC) and during maximal sniff manoeuvres (sniff PDI) at various levels of inspiratory vital capacity (VCin) served as parameters for diaphragmatic strength. Sniff PDI assessed at the various VCin levels were used to analyse the PDI/lung volume relation. RESULTS--Lung transplantation caused a reduction in lung volume, especially in the double lung transplant recipients. As a consequence sniff PDI was higher in the double lung transplant recipients than in the patients with COPD at all levels of VCin analysed. However, sniff PDI values analysed at comparable intrathoracic gas volumes were not reduced in the patients with COPD when compared with those who underwent lung transplantation. Bilateral twitch PDI values were similar in the patients with COPD and in the lung transplant recipients. In the single lung transplant recipients unilateral twitch PDI values were similar on the transplanted and the non-transplanted side. The relation between PDI and lung volume was similar in the patients with COPD and in the lung transplant recipients. CONCLUSIONS--In patients with COPD lung transplantation leads to an increase the maximal sniff induced PDI values by placing the diaphragm in a more favourable position for pressure generation. Since patients with COPD and postoperative lung transplant recipients showed similar PDI/lung volume relations, this suggests that chronic pulmonary hyperinflation does not cause major functional alterations of the diaphragm.
Nuclear Magnetic Resonance Imaging
Authors: A. Everette James
Journal: JAMA (1982)

NUCLEAR magnetic resonance (NMR) imaging is a technique by which the quantitative analysis of a biological structure or tissue sample may be determined. The various approaches to be discussed in this article all depend on the fact that certain atomic nuclei behave as small magnets. When these nuclei are placed in static magnetic fields, some will align themselves in the direction of the field. In this configuration they will rotate about the field direction (precess) at a frequency that is dependent on the strength of the applied magnetic field (Bo). If in this circumstance these aligned and precessing nuclei are exposed to an alternating magnetic field (radio frequency [RF]) of the same frequency, some of these nuclei will be forced from their equilibrium state to a higher energy level. When the interrogating RF is removed, the excited nuclei will emit the added energy and return to their former state. The
Additional Analysis of the Secondary End Point of Biochemical Recurrence Rate in a Phase 3 Trial (CS21) Comparing Degarelix 80mg Versus Leuprolide in Prostate Cancer Patients Segmented by Baseline Characteristics
Authors: Bertrand Tombal, Kurt Miller, Laurent Boccon-Gibod, Fritz Schröder, Neal Shore, E. David Crawford, Judd Moul, Jens-Kristian Jensen, Tine Kold Olesen, Bo-Eric Persson
Journal: European Urology (2009)
Obstructive sleep apnoea and metabolic syndrome: put CPAP efficacy in a more realistic perspective
Authors: Jean-Louis Pépin, Renaud Tamisier, Patrick Lévy
Journal: Thorax (2012)

Non-communicable Diseases, mainly cardiovascular diseases, cancer, diabetes and chronic respiratory diseases, are responsible for two-thirds of the 57 million annual deaths worldwide.1 Obesity and obstructive sleep apnoea (OSA) are among the key players involved in non-communicable diseases. Several studies have reported an independent association of OSA with the different components of the metabolic syndrome, particularly hypertension, insulin resistance and abnormal lipid metabolism.2 Both OSA and metabolic syndrome are associated with an increase risk in cardiovascular disease. Hence, rapidly accumulating data from both epidemiological and clinical studies3 have suggested that OSA is independently associated with alterations in glucose metabolism and with an increased risk of developing type 2 diabetes. Indeed, recent reports have indicated that more than 50% of patients with type 2 diabetes have OSA. Multiple mechanistic pathways contribute to the deteriorated plasma glucose/insulin homeostasis in OSA, the number one being sympathetic over activity,4 due to sleep fragmentation and intermittent hypoxia (figure 1). Independently of autonomic nervous system activation, in animal models intermittent hypoxia contributes to decreased glucose utilisation in oxidative muscle fibres.5 Intermittent hypoxia also seems to be responsible for increased beta-cell proliferation and cell death, the latter being due to oxidative stress.6 In fat tissue, chronic intermittent hypoxia (CIH) the hallmark of OSA exacerbate adipose tissue inflammation and lead to a dysregulated production of adipocytokines which may contribute to insulin resistance and could trigger non-alcoholic fatty liver disease (figure 1). We have demonstrated in morbid obesity that CIH is strongly associated with higher systemic inflammation (IL-6) and more severe fibrotic or inflammatory liver injuries.7 Visceral fat releases free fatty acids in the portal vein leading to accumulation of hepatic fat and development of hepatic insulin resistance. Regarding lipid abnormalities, intermittent hypoxia leads to an increase in serum cholesterol, to an up-regulation …
Late respiratory sequelae of blunt chest injury: a preliminary report.
Authors: C D Hanning, E Ledingham, I M Ledingham
Journal: Thorax (1981)

Eighty-six survivors of blunt chest injury were assessed for pre- and post-injury respiratory symptoms using a standardised questionnaire. A comparison was made between observed and expected symptom prevalence and lung function. Respiratory symptom prevalence after injury was greater than expected, 23 survivors (27%) claiming a persistent productive cough, 18 (21%) persistent wheezing, and 22 (26%) grade 2 dyspnoea. After injury persistent productive cough (p less than 0.05) and occasional wheezing (p less than 0.01) were more common among smokers and ex-smokers when compared with non-smokers. Mean forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were not statistically different from expected values. We concluded that respiratory sequelae of blunt chest injury are common and that smokers and ex-smokers are at particular risk.
Tumor Stroma–Derived Wnt5a Induces Differentiation of Basal Cell Carcinoma of <i>Ptch</i>-Mutant Mice via CaMKII
Authors: Frauke Nitzki, Arne Zibat, Simone König, Mark Wijgerde, Albert Rosenberger, Felix H. Brembeck, Per-Ole Carstens, Anke Frommhold, Anja Uhmann, Stefan Klingler, Julia Reifenberger, Tobias Pukrop, Fritz Aberger, Walter Schulz-Schaeffer, Heidi Hahn
Journal: Cancer Research (2010)

Basal cell carcinoma (BCC) is the most common skin tumor in humans. Although BCCs rarely metastasize, they can cause significant morbidity due to local aggressiveness. Approximately 20% of BCCs show signs of spontaneous regression. The understanding of molecular events mediating spontaneous regression has the potential to reduce morbidity of BCC and, potentially, other tumors, if translated into tumor therapies. We show that BCCs induced in conditional Ptch(flox/flox)ERT2(+/-) knockout mice regress with time and show a more differentiated phenotype. Differentiation is accompanied by Wnt5a expression in the tumor stroma, which is first detectable at the fully developed tumor stage. Coculture experiments revealed that Wnt5a is upregulated in tumor-adjacent macrophages by soluble signals derived from BCC cells. In turn, Wnt5a induces the expression of the differentiation marker K10 in tumor cells, which is mediated by Wnt/Ca(2+) signaling in a CaMKII-dependent manner. These data support a role of stromal Wnt5a in BCC differentiation and regression, which may have important implications for development of new treatment strategies for this tumor. Taken together, our results establish BCC as an easily accessible model of tumor regression. The regression of BCC despite sustained Hedgehog signaling activity seems to be mediated by tumor-stromal interactions via Wnt5a signaling.
Early Tumor Progression Associated with Enhanced EGFR Signaling with Bortezomib, Cetuximab, and Radiotherapy for Head and Neck Cancer
Authors: Athanassios Argiris, Austin G. Duffy, Shivaani Kummar, Nicole L. Simone, Yoshio Arai, Seungwon W. Kim, Susan F. Rudy, Vishnu R. Kannabiran, Xinping Yang, Minyoung Jang, Zhong Chen, Nanette Suksta, Theresa Cooley-Zgela, Susmita G. Ramanand, Aarif Ahsan, Mukesh K. Nyati, John J. Wright, Carter Van Waes
Journal: Clinical Cancer Research (2011)

Abstract Purpose: A phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy. Experimental Design: Patients with radiotherapy-naive stage IV or recurrent squamous cell carcinoma of the head and neck (SCCHN) were studied. Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m2) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensity-modulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC-1. Results: Seven patients were accrued before the study was terminated when five of six previously untreated patients with favorable prognosis oropharyngeal SCCHN progressed within 1 year (progression-free survival = 4.8 months; 95% CI, 2.6–6.9). Three patients each received bortezomib 0.7 or 1.0 mg/m2, without dose-limiting toxicities; one patient treated at 1.3 mg/m2 was taken off study due to recurring cetuximab infusion reaction and progressive disease (PD). Expected grade 3 toxicities included radiation mucositis (n = 4), dermatitis (n = 4), and rash (n = 1). SCCHN-related cytokines increased in serial serum specimens of patients developing PD (P = 0.029). Bortezomib antagonized cetuximab- and radiation-induced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC-1. Conclusions: Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination. Clin Cancer Res; 17(17); 5755–64. ©2011 AACR.
Renal failure as first manifestation of familial sarcoidosis
Authors: E. Pastor, J.M. Arriero, A.I. Gutiérrez, M.E. Barroso, R.J. Noguera, C. Muñoz, M.L. Porriño
Journal: European Respiratory Journal (2010)

amelioration unlikely.Secondly, the data were gathered from only a small group of patients willing to consent to two prolonged right heart catheterisation procedures 6 months apart.Nevertheless, this group was relatively homogeneous, with NYHA class III disease and high P ¯pa at presentation.Our results cannot be generalised, however, to other related PAH disease states, such as congenital heart disease or chronic pulmonary thromboembolism.Thirdly, our already lengthy study protocols (each lasting 2-3 h) did not allow time for cardiac output measurements at baseline and after each vasoactive drug, on each occasion of study.It is known from previous work that bosentan reduces pulmonary vascular resistance and increases cardiac output in PAH patients such as ours [10]; given this, the ability of ACh to produce greater vasodilatation after, compared with before, bosentan treatment clearly indicates improved endothelium-dependent dilator capacity after bosentan therapy.Finally, although IVUS measurements from control subjects were available to compare with the PAH patients, we did not perform (the relatively lengthy protocol for) pulmonary vascular reactivity studies in the healthy control subjects, to minimise risk to these volunteers.In summary, we report, for the first time in humans, that endothelin-1 receptor antagonism improves pulmonary microvascular endothelial function in patients with severe PAH.Although further confirmatory work is required to better elucidate the mechanistic pathways involved, our study provides in vivo evidence for a mechanism by which bosentan may contribute to its therapeutic effects in PAH patients.
A conversation with Lloyd Hollingsworth Smith Jr.
Authors: Ushma S. Neill
Journal: Journal of Clinical Investigation (2012)

We are joined by Dr. Lloyd Hollings­worth Smith Jr., known to most of his friends as Holly (Figure ​(Figure1),1), for the next in our series of Conversations with Giants in Medicine. Smith is recognized for leading the University of California, San Francisco, Department of Medicine as its chairman for 21 years between 1964 and 1985, whereupon his arrival, he quickly set about raising standards in patient care, teaching, and research. The full interview can be seen on the JCI website, http://www.jci.org/kiosk/cgm.
Genetic Diversity of Algal and Fungal Partners in Four Species of Umbilicaria (Lichenized Ascomycetes) Along a Transect of the Antarctic Peninsula
Authors: J. Romeike, T. Friedl, G. Helms, S. Ott
Journal: Molecular Biology and Evolution (2002)

Lichens from the genus Umbilicaria were collected across a 5,000-km transect through Antarctica and investigated for DNA sequence polymorphism in a region of 480–660 bp of the nuclear internal transcribed spacer region of ribosomal DNA. Sequences from both fungal (16 ascomycetes) and photosynthetic partners (22 chlorophytes from the genus Trebouxia) were determined and compared with homologs from lichens inhabiting more temperate, continental climates. The phylogenetic analyses reveal that Antarctic lichens have colonized their current habitats both through multiple independent colonization events from temperate embarkation zones and through recent long-range dispersal in the Antarctic of successful preexisting colonizers. Furthermore, the results suggest that relichenization—de novo establishment of the fungus-photosynthesizer symbiosis from nonlichenized algal and fungal cells—has occurred during the process of Antarctic lichen dispersal. Independent dispersal of algal and fungal cultures therefore can lead to a successful establishment of the lichen symbiosis even under harsh Antarctic conditions.