tbuckley/cabot-search huggingface dataset:
Kuhn's Paradigms: Are Those Closest to Treating Bladder Cancer the Last to Appreciate the Paradigm Shift?
Authors: Dean F. Bajorin, Harry W. Herr
Journal: Journal of Clinical Oncology (2011)

words, to encourage women to delay the prophylactic decision to a later date, when they are not simultaneously trying to cope with the decisions related to cancer therapy and are able to focus on the risks and benefits of loss of a healthy breast.The implications of this approach in relation to time lost from work, exposure to an additional surgical procedure, and the quality of the reconstruction will need to be investigated, but reasonable opportunities for a delayed procedure may occur after chemotherapy and before radiation, or for women who postpone reconstruction because of the need for postmastectomy radiotherapy at the time of a delayed reconstruction.The report by King et al 8 adds urgency to the need to resolve the paradox between progress in breast cancer therapy and the increasing use of a radical and unproven procedure.It is important that future studies of the consequences of bilateral mastectomy (with or without reconstruction) address not only the early complications of the procedure, but also the long-term impact on quality of life, including overall satisfaction, sexuality, and chronic pain, and balance this against the risk of adverse cancer outcomes and the risks of surveillance.It is clear that a new generation of prospective studies is required; ideally, these would enroll patients at the time when CPM is introduced (by patient or practitioner) and observe the patient until a point where quality of life outcomes are stable.To capture cancer-related outcomes efficiently, it would be most efficient to embed such a study into several parallel adjuvant therapy studies, in which long-term data on new cancer events and survival are already being captured.
Rate of change of end-stage renal disease treatment incidence 1978-1987--has there been selection?
Authors: S J Rosansky, K Jackson
Journal: Journal of the American Society of Nephrology (1992)

End-stage renal disease (ESRD) treatment rates in the United States have increased steadily since 1973. Decreasing selection against elderly patients with a poor prognostic primary cause of ESRD (i.e., diabetic nephropathy) may partly account for this increase in rates. To test this hypothesis, we calculated log ESRD treatment incidence (ESRDI) rates by four major primary causes of ESRD (diabetic nephropathy (DN), hypertensive nephropathy (HN), glomerulonephritis (GN), and cystic kidney disease (PC); two age groups (old (O), greater than 65 and young (Y), 15 to 44 yr of age) for black and white, male and female, new ESRD patients from 1978 to 1987. As predicted, summary log ESRDI slopes (produced by analysis of covariance) occurred in the following decreasing order, ODN (0.19), OGN = OHN = YDN (0.134). YHN = YPC = YGN (in white patients) = slope not significantly different from 0. Log ESRDI slopes for young black males and females with GN increased significantly between 1978 and 1987, possibly as a result of an increased incidence of GN. In conclusion, decreasing selection may be a factor in the continuing increase in the U.S. ESRD population.
Mitochondria in the diabetic heart
Authors: H. Bugger, E. D. Abel
Journal: Cardiovascular Research (2010)

Diabetes mellitus increases the risk of developing cardiovascular diseases such as coronary artery disease and heart failure. Studies have shown that the heart failure risk is increased in diabetic patients even after adjusting for coronary artery disease and hypertension. Although the cause of this increased heart failure risk is multifactorial, increasing evidence suggests that derangements in cardiac energy metabolism play an important role. In particular, abnormalities in cardiomyocyte mitochondrial energetics appear to contribute substantially to the development of cardiac dysfunction in diabetes. This review will summarize these abnormalities in mitochondrial function and discuss potential underlying mechanisms.
Mechanisms Underlying the Increase in Force and Ca <sup>2+</sup> Transient That Follow Stretch of Cardiac Muscle
Authors: Bernardo V. Alvarez, Néstor G. Pérez, Irene L. Ennis, María C. Camilión de Hurtado, Horacio E. Cingolani
Journal: Circulation Research (1999)

Abstract —Myocardial stretch produces an increase in developed force (DF) that occurs in two phases: the first (rapidly occurring) is generally attributed to an increase in myofilament calcium responsiveness and the second (gradually developing) to an increase in [Ca 2+ ] i . Rat ventricular trabeculae were stretched from ≈88% to ≈98% of L max , and the second force phase was analyzed. Intracellular pH, [Na + ] i , and Ca 2+ transients were measured by epifluorescence with BCECF-AM, SBFI-AM, and fura-2, respectively. After stretch, DF increased by 1.94±0.2 g/mm 2 ( P &lt;0.01, n=4), with the second phase accounting for 28±2% of the total increase ( P &lt;0.001, n=4). During this phase, SBFI 340/380 ratio increased from 0.73±0.01 to 0.76±0.01 ( P &lt;0.05, n=5) with an estimated [Na + ] i rise of ≈6 mmol/L. [Ca 2+ ] i transient, expressed as fura-2 340/380 ratio, increased by 9.2±3.6% ( P &lt;0.05, n=5). The increase in [Na + ] i was blocked by 5-( N -ethyl- N -isopropyl)-amiloride (EIPA). The second phase in force and the increases in [Na + ] i and [Ca 2+ ] i transient were blunted by AT 1 or ET A blockade. Our data indicate that the second force phase and the increase in [Ca 2+ ] i transient after stretch result from activation of the Na + /H + exchanger (NHE) increasing [Na + ] i and leading to a secondary increase in [Ca 2+ ] i transient. This reflects an autocrine-paracrine mechanism whereby stretch triggers the release of angiotensin II, which in turn releases endothelin and activates the NHE through ET A receptors.
Fragile Histidine Triad–Mediated Tumor Suppression of Lung Cancer by Targeting Multiple Components of the Ras/Rho GTPase Molecular Switch
Authors: Gitanjali Jayachandran, Ji-ichiro Sazaki, Masahito Nishizaki, Kai Xu, Luc Girard, John D. Minna, Jack A. Roth, Lin Ji
Journal: Cancer Research (2007)

Abstract The fragile histidine triad (FHIT) gene has been shown to function as a tumor suppressor gene in vitro and in vivo. However, the mechanism of its action is still largely unknown. To elucidate the molecular mechanism and biological pathway in FHIT-mediated tumor suppression, we used a complementary gene and protein expression profiling with DNA microarray and ProteinChip technologies to quantitatively monitor cellular changes in gene and protein expression and discover the molecular targets of FHIT in non–small cell lung carcinoma (NSCLC) cells. The Ras/Rho signaling pathway was identified as one of the unique biological pathways associated with FHIT activity. A significantly down-regulated expression of genes and proteins of multiple key components in the Ras/Rho GTPases molecular switch, including Ran, Rab, Rac, Rap, and Ral, was observed on gene and protein expression profiles and further validated by Western blot analysis. Ectopic activation of FHIT in FHIT-deficient H1299 cells also significantly reduced the invasive potential of tumor cells by down-regulating expression of RhoC, a potential marker of tumor cell invasion and metastases. A simultaneous knockdown of the expression of several key Ras/Rho signaling molecules using gene-specific small interfering RNAs (RHO-siRNA) targeting selected Rab11, Rac1, and Rap1 genes significantly inhibited tumor cell growth and induced apoptosis in NSCLC cells in vitro, and a local injection of RHO-siRNAs complexed with N-[1-(2,3-dioleoyloxyl)propyl]-N,N,N-trimethylammoniummethyl sulfate:cholesterol nanoparticles inhibited tumor growth in A549 tumor xenografts in mice, mimicking the AdFHIT-mediated tumor-suppressing effect. These results suggest a new role of FHIT in down-regulating the Ras/Rho GTPase-associated oncogenic signaling pathway. [Cancer Res 2007;67(21):10379–88]
Quantifying Selection Acting on a Complex Trait Using Allele Frequency Time Series Data
Authors: C. J. R. Illingworth, L. Parts, S. Schiffels, G. Liti, V. Mustonen
Journal: Molecular Biology and Evolution (2011)

When selection is acting on a large genetically diverse population, beneficial alleles increase in frequency.This fact can be used to map quantitative trait loci by sequencing the pooled DNA from the population at consecutive time points and observing allele frequency changes.Here, we present a population genetic method to analyze time series data of allele frequencies from such an experiment.Beginning with a range of proposed evolutionary scenarios, the method measures the consistency of each with the observed frequency changes.Evolutionary theory is utilized to formulate equations of motion for the allele frequencies, following which likelihoods for having observed the sequencing data under each scenario are derived.Comparison of these likelihoods gives an insight into the prevailing dynamics of the system under study.We illustrate the method by quantifying selective effects from an experiment, in which two phenotypically different yeast strains were first crossed and then propagated under heat stress (Parts L, Cubillos FA, Warringer J,. 2011.Revealing the genetic structure of a trait by sequencing a population under selection.Genome Res).From these data, we discover that about 6% of polymorphic sites evolve nonneutrally under heat stress conditions, either because of their linkage to beneficial (driver) alleles or because they are drivers themselves.We further identify 44 genomic regions containing one or more candidate driver alleles, quantify their apparent selective advantage, obtain estimates of recombination rates within the regions, and show that the dynamics of the drivers display a strong signature of selection going beyond additive models.Our approach is applicable to study adaptation in a range of systems under different evolutionary pressures.
Revisiting Hippocrates
Authors: D Graham
Journal: JAMA (2000)

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Fc Receptor-Like Molecules
Authors: Randall S. Davis
Journal: Annual Review of Immunology (2007)

Discovery of a large family of Fc receptor-like (FCRL) molecules, homologous to the well-known receptors for the Fc portion of immunoglobulin (FCR), has uncovered an impressive abundance of immunoglobulin superfamily (IgSF) genes in the human 1q21-23 chromosomal region and revealed significant diversity for these genes between humans and mice. The observation that FCRL representatives are members of an ancient multigene family that share a common ancestor with the classical FCR is underscored by their linked genomic locations, gene structure, shared extracellular domain composition, and utilization of common cytoplasmic tyrosine-based signaling elements. In contrast to the conventional FCR, however, FCRL molecules possess diverse extracellular frameworks, autonomous or dual signaling properties, and preferential B lineage expression. Most importantly, there is no strong evidence thus far to support a role for them as Ig-binding receptors. These characteristics, in addition to their identification in malignancies and autoimmune disorders, predict a fundamental role for these receptors as immunomodulatory agents in normal and subverted B lineage cells.
Increased Intestinal Permeability Is Associated with the Development of Multiple Organ Dysfunction Syndrome in Critically Ill ICU Patients
Authors: CHRISTOPHER J. DOIG, LLOYD R. SUTHERLAND, J. DEAN SANDHAM, GORDON H. FICK, MARJA VERHOEF, JON B. MEDDINGS
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

We conducted a prospective, observational cohort study designed to compare intestinal permeability (IP) and development of multiple organ dysfunction syndrome (MODS) in a subset of critically ill patients in an intensive care unit (ICU). All patients with an expected ICU stay of 72 h or more were entered into the study, and IP was determined on a daily basis whenever possible from the urinary fractional excretion of orally administered lactulose and mannitol (LMR). Forty-seven consecutive patients were studied, and 28 developed MODS either at the time of admission or during their ICU course. These patients, as a group, had significantly worse IP at admission than did a non-MODS cohort (LnLMR: − 2.10 ± 1.10 versus − 3.26 ± 0.83). Those patients who developed MODS following admission also had a significantly greater admission IP than did the non-MODS group ( − 2.51 ± 0.85). Differences in IP between cohorts could not be explained by differences in the incidence of systemic inflammatory response syndrome (SIRS)/sepsis or shock. With multivariate regression analysis, the only parameter present on admission that was predictive of subsequent MODS was IP. Differences in IP and the severity of organ dysfunction were also present (MODS severity mild: − 3.01 ± 0.72; moderate: − 1.97 ± 0.69; and severe: − 1.12 ± 0.96). Patients who developed MODS had a persistently abnormal IP during their ICU stay, and a significantly delayed improvement in their IP compared with the non-MODS cohort. We conclude that the development of MODS is associated with an abnormal and severe derangement of IP that is detectable prior to the onset of the syndrome. This observation lends credence to the premise that gastrointestinal (GI) dysfunction may be causally associated with the development of MODS in the critically ill patient.
Benefits and Consequences for the Poor and the Disabled
Authors: Rachel A Elliott, Sumit R Majumdar, Muriel R Gillick, Stephen B Soumerai
Journal: New England Journal of Medicine (2005)

The new Medicare Part D will improve access to medications for millions of Americans. One subgroup of beneficiaries, however, may inadvertently be made worse off: the 7.2 million people enrolled in both Medicaid (because they are poor) and Medicare (because they are elderly or disabled). These beneficiaries, known as the dually eligible, already receive drug benefits through state-run Medicaid programs; but as of 2006, they will be required to enroll in Medicare Part D.Moving the dually eligible recipients of drug benefits to new federal programs raises several concerns: these beneficiaries may have problems making the transition and negotiating the . . .
New loci associated with kidney function and chronic kidney disease
Authors: Anna Köttgen, Cristian Pattaro, Carsten A Böger, Christian Fuchsberger, Matthias Olden, Nicole L Glazer, Afshin Parsa, Xiaoyi Gao, Qiong Yang, Albert V Smith, Jeffrey R O'Connell, Man Li, Helena Schmidt, Toshiko Tanaka, Aaron Isaacs, Shamika Ketkar, Shih-Jen Hwang, Andrew D Johnson, Abbas Dehghan, Alexander Teumer, Guillaume Paré, Elizabeth J Atkinson, Tanja Zeller, Kurt Lohman, Marilyn C Cornelis, Nicole M Probst-Hensch, Florian Kronenberg, Anke Tönjes, Caroline Hayward, Thor Aspelund, Gudny Eiriksdottir, Lenore J Launer, Tamara B Harris, Evadnie Rampersaud, Braxton D Mitchell, Dan E Arking, Eric Boerwinkle, Maksim Struchalin, Margherita Cavalieri, Andrew Singleton, Francesco Giallauria, Jeffrey Metter, Ian H de Boer, Talin Haritunians, Thomas Lumley, David Siscovick, Bruce M Psaty, M Carola Zillikens, Ben A Oostra, Mary Feitosa, Michael Province, Mariza de Andrade, Stephen T Turner, Arne Schillert, Andreas Ziegler, Philipp S Wild, Renate B Schnabel, Sandra Wilde, Thomas F Munzel, Tennille S Leak, Thomas Illig, Norman Klopp, Christa Meisinger, H-Erich Wichmann, Wolfgang Koenig, Lina Zgaga, Tatijana Zemunik, Ivana Kolcic, Cosetta Minelli, Frank B Hu, Åsa Johansson, Wilmar Igl, Ghazal Zaboli, Sarah H Wild, Alan F Wright, Harry Campbell, David Ellinghaus, Stefan Schreiber, Yurii S Aulchenko, Janine F Felix, Fernando Rivadeneira, Andre G Uitterlinden, Albert Hofman, Medea Imboden, Dorothea Nitsch, Anita Brandstätter, Barbara Kollerits, Lyudmyla Kedenko, Reedik Mägi, Michael Stumvoll, Peter Kovacs, Mladen Boban, Susan Campbell, Karlhans Endlich, Henry Völzke, Heyo K Kroemer, Matthias Nauck, Uwe Völker, Ozren Polasek, Veronique Vitart, Sunita Badola, Alexander N Parker, Paul M Ridker, Sharon L R Kardia, Stefan Blankenberg, Yongmei Liu, Gary C Curhan, Andre Franke, Thierry Rochat, Bernhard Paulweber, Inga Prokopenko, Wei Wang, Vilmundur Gudnason, Alan R Shuldiner, Josef Coresh, Reinhold Schmidt, Luigi Ferrucci, Michael G Shlipak, Cornelia M van Duijn, Ingrid Borecki, Bernhard K Krämer, Igor Rudan, Ulf Gyllensten, James F Wilson, Jacqueline C Witteman, Peter P Pramstaller, Rainer Rettig, Nick Hastie, Daniel I Chasman, W H Kao, Iris M Heid, Caroline S Fox
Journal: Nature Genetics (2010)
Population Genetics of IFIH1: Ancient Population Structure, Local Selection, and Implications for Susceptibility to Type 1 Diabetes
Authors: M. Fumagalli, R. Cagliani, S. Riva, U. Pozzoli, M. Biasin, L. Piacentini, G. P. Comi, N. Bresolin, M. Clerici, M. Sironi
Journal: Molecular Biology and Evolution (2010)

The human interferon induced with helicase C domain 1 (IFIH1) gene encodes a sensor of double-strand RNA involved in innate immunity against viruses, indicating that this gene is a likely target of virus-driven selective pressure. Notably, IFIH1 also plays a role in autoimmunity, as common and rare polymorphisms in this gene have been associated with type 1 diabetes (T1D). We analyzed the evolutionary history of IFIH1 in human populations. Results herein suggest that two major IFIH1 haplotype clades originated from ancestral population structure (or balancing selection) in the African continent and that local selective pressures have acted on the gene. Specifically, directional selection in Europe and Asia resulted in the spread of a common IFIH1 haplotype carrying a derived His460 allele. This variant changes a highly conserved arginine residue in the helicase domain, possibly conferring altered specificity in viral recognition. An alternative common haplotype has swept to high frequency in South Americans as a result of recent positive selection. Previous studies suggested that a portion of risk alleles for autoimmune diseases could have been maintained in humans as they conferred a selective advantage against infections. This is not the case for IFIH1, as population genetic differentiation and haplotype analyses indicated that the T1D susceptibility alleles behaved as neutral or nearly neutral polymorphisms. Our findings suggest that variants in IFIH1 confer different susceptibility to diverse viral infections and provide insight into the relationship between adaptation to past infection and predisposition to autoimmunity in modern populations.
Direct actions of cocaine on cardiac cellular electrical activity.
Authors: D A Przywara, G E Dambach
Journal: Circulation Research (1989)

The hypothesis that cocaine has Class I-type antiarrhythmic drug effects was tested in tissues isolated from rabbit heart with standard microelectrode methods. Propranolol (1 microM) was used to block beta-adrenergic effects. The actions of cocaine on cellular electrophysiology were concentration- and time-dependent and were reversible. In paced right atrial (RA) and right ventricular papillary (RVP) tissues, cocaine produced a profound prolongation of the effective refractory period (ERP) assessed by either premature stimulation or minimum pacing interval. ERP was increased up to eightfold in RA tissue and doubled in RVP tissue by 60 microM cocaine. This concentration of cocaine depressed action potential phase 0 depolarization 80% in RA tissue and 53% in RVP tissue but had no effect on resting membrane potentials. Automaticity was moderately depressed in sinus node (34% decrease in rate) but not in tricuspid valve cells. Phase 0 depolarization was not altered in these spontaneously active slow-response cells. Repolarization was depressed in RA, tricuspid valve, and sinus node cells leading to a twofold increase in action potential duration during exposure to cocaine. Evidence from the effects on cellular action potentials suggests that cocaine affects both fast Na+ channels and repolarizing K+ but not Ca2+ channels. We conclude that cocaine has Class I-type activity and the effects on ERP are extreme.
<i>Pneumocystis carinii</i> Pneumonia: A Major Complication of Immunosuppressive Therapy in Patients with Wegener's Granulomatosis
Authors: Frederick P. Ognibene, James H. Shelhamer, Gary S. Hoffman, Gail S. Kerr, Debra Reda, Anthony S. Fauci, Randi Y. Leavitt
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

The risk factors and clinical and laboratory parameters in Pneumocystis carinii pneumonia in patients with Wegener's granulomatosis have not been well characterized. We undertook a retrospective chart review of all patients with a diagnosis of Wegener's granulomatosis and P. carinii pneumonia who were followed at the National Institute of Allergy and Infectious Diseases of the National Institutes of Health. The chart review focused on clinical, laboratory, and roentgenologic evidence of P. carinii pneumonia. Eleven cases of P. carinii pneumonia were diagnosed in some 180 patients with Wegener's granulomatosis, for an overall incidence of approximately 6%. All patients developed P. carinii pneumonia either during the initial course of treatment or during therapy for recurrent Wegener's granulomatosis. All patients were receiving daily glucocorticoids and a second immunosuppressive therapy. Lymphocytopenia was noted in all patients, with a mean +/- SEM total lymphocyte count of 303 +/- 69 cells/microL. All patients tested (10 of 11) were seronegative for human immunodeficiency virus (HIV) infection. Eight presented with worsening chest roentgenograms compared with baseline, whereas three presented with normal chest roentgenograms. We conclude that P. carinii is a common opportunistic pathogen in patients with Wegener's granulomatosis receiving immunosuppressive therapy. Therapeutic immunosuppression (daily glucocorticoids and immunosuppressive agents) and the resultant lymphocytopenia, as well as the lymphocyte and monocyte functional abnormalities caused by glucocorticoids, may be the most likely factors predisposing to P. carinii pneumonia in patients with Wegener's granulomatosis. Based on our data, all patients with Wegener's granulomatosis should be given chemoprophylaxis against P. carinii while they are receiving daily glucocorticoids.(ABSTRACT TRUNCATED AT 250 WORDS)