tbuckley/cabot-search huggingface dataset:
KLF4-Mediated Negative Regulation of IFITM3 Expression Plays a Critical Role in Colon Cancer Pathogenesis
Authors: Dawei Li, Zhihai Peng, Huamei Tang, Ping Wei, Xiangyu Kong, Dongwang Yan, Fei Huang, Qiang Li, Xiangdong Le, Qi Li, Keping Xie
Journal: Clinical Cancer Research (2011)

IFITM3, an IFN-inducible gene, is overexpressed in human colorectal cancer. In this study, we sought to determine the clinical significance and underlying mechanisms of its dysregulated expression in human colon tumor specimens and murine models of this disease.IFITM3 expression in a tissue microarray of tumor and matched normal colon tissue specimens and lymph node metastasis specimens obtained from 203 patients with colon cancer was measured immunohistochemically.IFITM3 was expressed at higher levels in colon tumors and, particularly, nodal metastases than in normal colon tissue. A Cox proportional hazards model showed that IFITM3 expression was an independent prognostic factor for disease-free survival in patients with colon cancer. Knockdown of IFITM3 expression by a specific siRNA significantly suppressed the proliferation, colony formation, migration, and invasion of colon cancer cells in vitro and tumor growth and metastasis in a xenograft model. Restored expression of KLF4, a putative tumor suppressor, downregulated IFITM3 expression in colon cancer cells in vitro. Two KLF4-binding sites in the IFITM3 promoter bound specifically to KLF4 protein in a chromatin immunoprecipitation assay and promoter mutagenesis analyses. Specific deletion of KLF4 led to IFITM3 overexpression in colon mucosa in Villin-Cre(+);Klf4(fl/fl) mice. An inverse correlation between loss of KLF4 expression and IFITM3 overexpression was evident in human colon tumors.These clinical and mechanistic findings indicate that IFITM3 is a direct transcriptional target of KLF4 and that dysregulated KLF4 expression leads to aberrant IFITM3 expression, thus contributing to colon cancer progression and metastasis.
Virtual hospital for HIV patients halves consultation times
Authors: A. Garcia Rada
Journal: BMJ (2011)

A home telemedicine system for patients with stable HIV infection has proved popular among patients and has reduced consultation times by half, say doctors in Barcelona and Madrid.

The Virtual Hospital was developed by a team from the University of Barcelona Hospital Clinic and the Bioengineering and Telemedicine Unit of the Technical University of Madrid.

It offers four main services: virtual consultations, a telepharmacy, a virtual library, and a virtual community. Patients get their drug treatments by post and can book consultations online, …
Concomitant Alterations of Sodium Flux and Membrane Phospholipid Metabolism in Red Blood Cells: Studies in Hereditary Spherocytosis*
Authors: Harry S. Jacob, Manfred L. Karnovsky
Journal: Journal of Clinical Investigation (1967)

The role of membrane phosphatides in transport processes has been investigated in red cells from splenectomized patients with hereditary spherocytosis (HS). Incorporation of inorganic (32)phosphate into the membrane phosphatides of HS red cells was approximately twice normal, coinciding with the nearly twofold increment in flux of sodium ions in the cells.A consistent, inordinate increase in specific activity of a chromatographic fraction containing phosphatidylserine provided the bulk of the over-all increase in labeling of HS red cell phosphatides. The specific activity of phosphatidic acid was increased but not consistently. Radioactivity of the "acidic phosphatides" (phosphatidylserine and phosphatidic acid fractions) decreased, in general, when the sodium flux was low, i.e., when the cells were suspended in media of low sodium content. When the cation flux was elevated (hypotonic media), there was a marked (ca. 35%) increase in the labeling of phosphatidylserine fractions. Normal red cells whose permeability to cations was increased by exposure to 0.5 N butanol also exhibited increased labeling of acidic phosphatides. Considerations of the stoichiometry of cation transport and phosphatide labeling make it unlikely that phospholipids act directly as carrier molecules for cations in red cell membranes. On the other hand, the involvement of these lipid substances in cation movements is substantiated by correlating several different states of sodium flux with the labeling of the phosphatidic acid and phosphatidylserine fractions.
Virtual action: O'Regan &amp; Noë meet Bergson
Authors: Stephen E. Robbins
Journal: Behavioral and Brain Sciences (2004)

Bergson, writing in 1896, anticipated “sensorimotor contingencies” under the concept that perception is “virtual action.” But to explain the external image, he embedded this concept in a holographic framework where time-motion is an indivisible and the relation of subject/object is in terms of time. The target article's account of qualitative visual experience falls short for lack of this larger framework. [Objects] send back, then, to my body, as would a mirror, their eventual influence; they take rank in an order corresponding to the growing or decreasing powers of my body. The objects which surround my body reflect its possible action upon them. – Henri Bergson (1896/1912, pp. 6–7)
Sarcoplasmic reticulum and mitochondria in cardiac pathophysiology
Authors: D. Garcia-Dorado, H. M. Piper, D. A. Eisner
Journal: Cardiovascular Research (2007)

Muscle cells, and in particular cardiomyocytes, consume a large amount of chemical energy to produce mechanical work. Myofilament contraction is regulated and synchronized within the cell by rapid, transient changes in the cytosolic Ca2+ concentration. Most of this calcium is released from the sarcoplasmic reticulum (SR), which has a large surface for Ca2+ transport, in close contact with the myofilaments. In between the myofilaments, cardiomyocytes are packed with mitochondria. These generate the energy needed for myofilament contraction, but serve also as an additional store for Ca2+. Thus, SR and mitochondria interact physiologically to control cellular Ca2+ homeostasis. It is partly through the Ca2+ loading of the mitochondria that their energy production is matched with the contractile energy demand.

Mitochondria are now recognized as an essential effector structure determining cell death and survival. This is not only because of their central role in cellular energy metabolism, but also as key players in survival and death signalling. Alterations in the function of the SR are now known to be of primary importance for the development of hypertrophy and heart failure and in the genesis of life-threatening arrhythmias. Therefore, interaction between SR and mitochondria not only determines cardiomyocyte function under physiological conditions, but also is relevant for the development of cardiomyocyte dysfunction or death under pathophysiological conditions. The present Spotlight Issue of Cardiovascular Research aims to update our understanding of these important and rapidly evolving aspects of cardiac physiology and pathophysiology through a series of invited reviews and original contributions.

In this issue, Orchard and Brette review the structure and function of t-tubules, their contribution to Ca2+ transients in cooperation with the SR, and the pathophysiological importance of their remodelling in … 

*Corresponding author. Tel: +34 93 489 4038; fax: +34 93 489 4032. E-mail address : dgdorado{at}ir.vhebron.net
Of skyhooks and the coevolution of scientific disciplines
Authors: Donald R. Franceschetti
Journal: Behavioral and Brain Sciences (1999)

The history of the natural sciences repeatedly shows that the unification of a higher level theory with a lower level theory by reduction does not eliminate the need for the higher level theory nor preclude its further development, leading to changes in the understanding of the lower level. The radical neuron doctrine proposes that the future science of psychology or linguistics will derive principally from the evolution of understanding at the neural level and not from current theories based on the observation of behavior. It is far more likely that the two bodies of theory will coevolve in semiautonomous fashion.
A Randomized Double-Blind, Placebo-Controlled Multicenter Study to Evaluate the Efficacy and Safety of Two Doses of the Tramadol Orally Disintegrating Tablet for the Treatment of Premature Ejaculation Within Less Than 2 Minutes
Authors: David Bar-Or, Kristin M. Salottolo, Alessandro Orlando, James V. Winkler
Journal: European Urology (2011)
Mechanisms of Discordant Alternans and Induction of Reentry in Simulated Cardiac Tissue
Authors: Zhilin Qu, Alan Garfinkel, Peng-Sheng Chen, James N. Weiss
Journal: Circulation (2000)

Background —T-wave alternans, which is associated with the genesis of cardiac fibrillation, has recently been related to discordant action potential duration (APD) alternans. However, the cellular electrophysiological mechanisms responsible for discordant alternans are poorly understood. Methods and Results —We simulated a 2D sheet of cardiac tissue using phase 1 of the Luo-Rudy cardiac action potential model. A steep (slope &gt;1) APD restitution curve promoted concordant APD alternans and T-wave alternans without QRS alternans. When pacing was from a single site, discordant APD alternans occurred only when the pacing rate was fast enough to engage conduction velocity (CV) restitution, producing both QRS and T-wave alternans. Tissue heterogeneity was not required for this effect. Discordant alternans markedly increases dispersion of refractoriness and increases the ability of a premature stimulus to cause localized wavebreak and induce reentry. In the absence of steep APD restitution and of CV restitution, sustained discordant alternans did not occur, but reentry could be induced if there was marked electrophysiological heterogeneity. Both discordant APD alternans and preexisting APD heterogeneity facilitate reentry by causing the waveback to propagate slowly. Conclusion —Discordant alternans arises dynamically from APD and CV restitution properties and markedly increases dispersion of refractoriness. Preexisting and dynamically induced (via restitution) dispersion of refractoriness independently increase vulnerability to reentrant arrhythmias. Reduction of dynamically induced dispersion by appropriate alteration of electrical restitution has promise as an antiarrhythmic strategy.
A Cell-Based Phenotypic Assay to Identify Cardioprotective Agents
Authors: Stephanie Guo, Adam Olm-Shipman, Andrew Walters, William R. Urciuoli, Stefanie Devito, Sergiy M. Nadtochiy, Andrew P. Wojtovich, Paul S. Brookes
Journal: Circulation Research (2012)

Rationale: Tissue ischemia/reperfusion (IR) injury underlies several leading causes of death such as heart-attack and stroke. The lack of clinical therapies for IR injury may be partly due to the difficulty of adapting IR injury models to high-throughput screening (HTS). Objective: To develop a model of IR injury that is both physiologically relevant and amenable to HTS. Methods and Results: A microplate-based respirometry apparatus was used. Controlling gas flow in the plate head space, coupled with the instrument's mechanical systems, yielded a 24-well model of IR injury in which H9c2 cardiomyocytes were transiently trapped in a small volume, rendering them ischemic. After initial validation with known protective molecules, the model was used to screen a 2000-molecule library, with post-IR cell death as an end point. P o 2 and pH monitoring in each well also afforded metabolic data. Ten protective, detrimental, and inert molecules from the screen were subsequently tested in a Langendorff-perfused heart model of IR injury, revealing strong correlations between the screening end point and both recovery of cardiac function (negative, r 2 =0.66) and infarct size (positive, r 2 =0.62). Relationships between the effects of added molecules on cellular bioenergetics and protection against IR injury were also studied. Conclusions: This novel cell-based assay can predict either protective or detrimental effects on IR injury in the intact heart. Its application may help identify therapeutic or harmful molecules.
Pulmonary perfusion quantified by electron-beam computed tomography: effects of hypoxia and inhaled NO
Authors: A.T. Jones, D.M. Hansell, T.W. Evans
Journal: European Respiratory Journal (2003)

Patients with acute lung injury may benefit from the manipulation of pulmonary blood flow using inhaled nitric oxide (iNO) to optimise ventilation/perfusion matching. Current techniques for studying changes in regional pulmonary perfusion are difficult to apply clinically. This study therefore investigated the potential of electron-beam computed tomography (EBCT) to quantify the effects of hypoxia and iNO on regional pulmonary perfusion in five healthy subjects. Contrast-enhanced sections were obtained sequentially under conditions of normoxia, hypoxia (fractional concentration of oxygen in inspired gas (<i>F</i><sub>I,O<sub>2</sub></sub>) 0.12) and hypoxia, with iNO (14.8 parts per million (ppm)) administered during inspiration in the supine position. Regions of interest were placed along the nondependent to dependent axis and values for relative perfusion derived. Under normoxic conditions a vertical gradient of perfusion existed, which became less apparent due to increased perfusion in nondependent regions after the induction of hypoxia (<i>F</i><sub>I,O<sub>2</sub></sub> 0.12). The addition of iNO (<i>F</i><sub>I,O<sub>2</sub></sub> 0.12 and NO 14.8 ppm) increased perfusion in all regions of the lung section, suggesting redistribution of pulmonary perfusion from other regions of the lung. Absolute values of perfusion were comparable to those documented with existing techniques. The use of a high spatial-resolution technique confirmed the presence of marked perfusion heterogeneity between anatomically close regions of lung.
Diminished virulence of a sar-/agr- mutant of Staphylococcus aureus in the rabbit model of endocarditis.
Authors: A L Cheung, K J Eberhardt, E Chung, M R Yeaman, P M Sullam, M Ramos, A S Bayer
Journal: Journal of Clinical Investigation (1994)

Microbial pathogenicity in Staphylococcus aureus is a complex process involving a number of virulence genes that are regulated by global regulatory systems including sar and agr. To evaluate the roles of these two loci in virulence, we constructed sar-/agr- mutants of strains RN6390 and RN450 and compared their phenotypic profiles to the corresponding single sar- and agr- mutants and parents. The secretion of all hemolysins was absent in the sar-/agr- mutants while residual beta-hemolysin activity remained in single agr- mutants. The fibronectin binding capacity was significantly diminished in both single sar- mutants and double mutants when compared with parents while the reduction in fibrinogen binding capacity in the double mutants was modest. In the rabbit endocarditis model, there was a significant decrease in both infectivity rates and intravegetation bacterial densities with the double mutant as compared to the parent (RN6390) at 10(3)-10(6) CFU inocula despite comparable levels of early bacteremia among various challenge groups. Notably, fewer bacteria in the double mutant group adhered to valvular vegetations at 30 min after challenge (10(6) CFU) than the parent group. These studies suggest that both the sar and agr loci are involved in initial valvular adherence, intravegetation persistence and multiplication of S. aureus in endocarditis.
Enhanced Skin Self-examination: A Novel Approach to Skin Cancer Monitoring and Follow-up
Authors: Monika Janda, Lois J. Loescher, H. Peter Soyer
Journal: JAMA Dermatology (2013)

Advances in mobile telephone technology and available dermoscopic attachments for mobile telephones have created a unique opportunity for consumer-initiated mobile teledermoscopy. At least 2 companies market a dermoscope attachment for an iPhone (Apple), forming a mobile teledermoscope. These devices and the corresponding software applications (apps) enable (1) lesion magnification (at least ×20) and visualization with polarized light; (2) photographic documentation using the telephone camera; (3) lesion measurement (ruler); (4) adding of image and lesion details; and (5) e-mail data to a teledermatologist for review. For lesion assessment, the asymmetry-color (AC) rule has 94% sensitivity and 62 specificity for melanoma identification by consumers [1]. Thus, consumers can be educated to recognize asymmetry and color patterns in suspect lesions. However, we know little about consumers' use of mobile teledermoscopy for lesion assessment.
Alcohol intake modulates the effect of a polymorphism of the cholesteryl ester transfer protein gene on plasma high density lipoprotein and the risk of myocardial infarction.
Authors: F Fumeron, D Betoulle, G Luc, I Behague, S Ricard, O Poirier, R Jemaa, A Evans, D Arveiler, P Marques-Vidal
Journal: Journal of Clinical Investigation (1995)

A polymorphism of the CETP gene (CETP/TaqIB) with two alleles B1 (60%) and B2 (40%) has been investigated in relation to lipid variables and the risk of myocardial infarction in a large case-control study (ECTIM) of men aged 25-64. No association was observed between the polymorphism and LDL or VLDL related lipid variables. Conversely, B2 carriers had reduced levels of plasma CETP (P < 0.0001) and increased levels of HDL cholesterol (P < 0.0001) and of other HDL related lipid variables. The effects of the polymorphism on plasma CETP and HDL cholesterol were independent, suggesting the presence of at least two functional variants linked to B2. A search for these variants on the coding sequence of the CETP gene failed to identify them. The effect of B2 on plasma HDL cholesterol was absent in subjects drinking < 25 grams/d of alcohol but increased commensurably, with higher values of alcohol consumption (interaction: P < 0.0001). A similar interaction was not observed for plasma CETP. The odds-ratio for myocardial infarction of B2 homozygotes decreased from 1.0 in nondrinkers to 0.34 in those drinking 75 grams/d or more. These results provide the first demonstration of a gene-environment interaction affecting HDL cholesterol levels and coronary heart disease risk.
The Influence of Muscle Physiology and Advanced Technology on Sports Performance
Authors: Richard R. Neptune, Craig P. McGowan, John M. Fiandt
Journal: Annual Review of Biomedical Engineering (2009)

Muscle mechanical output such as force and power are governed by highly nonlinear intrinsic muscle properties associated with different muscle fiber types and are influenced by training and age. Many of the interactions between these properties pose trade-offs such that an individual's anthropometrics and muscle morphology may allow an athlete to excel in one sport but not in others. Advanced modeling and simulation techniques are powerful tools to gain insight into performance limits, optimal equipment designs, and mechanisms that may lead to injury. Recent technological innovations have produced faster running tracks, bicycles, speed skates, and swimming pools. This review discusses the influence of intrinsic muscle properties in sports and how advanced technology can be used to extend the limits of human performance.
Screening and Treatment of Thyroid Dysfunction: An Evidence Review for the U.S. Preventive Services Task Force
Authors: J. Bruin Rugge, Christina Bougatsos, Roger Chou
Journal: Annals of Internal Medicine (2014)

In 2004, the U.S. Preventive Services Task Force found insufficient evidence to recommend thyroid screening.To update the 2004 U.S. Preventive Services Task Force review on the benefits and harms of screening and treatment of subclinical and undiagnosed overt hypothyroidism and hyperthyroidism in adults without goiter or thyroid nodules.MEDLINE and Cochrane databases through July 2014.Randomized, controlled trials and observational studies of screening and treatment.One investigator abstracted data, and a second investigator confirmed; 2 investigators independently assessed study quality.No study directly assessed benefits and harms of screening versus no screening. For subclinical hypothyroidism (based on thyroid-stimulating hormone levels of 4.1 to 11.0 mIU/L), 1 fair-quality cohort study found that treatment of subclinical hypothyroidism was associated with decreased risk for coronary heart disease events versus no treatment. No study found that treatment was associated with improved quality of life, cognitive function, blood pressure, or body mass index versus no treatment. Effects of treatment versus no treatment showed potential beneficial effects on lipid levels, but effects were inconsistent, not statistically significant in most studies, and of uncertain clinical significance (difference, -0.7 to 0 mmol/L [-28 to 0 mg/dL] for total cholesterol levels and -0.6 to 0.1 mmol/L [-22 to 2 mg/dL] for low-density lipoprotein cholesterol levels). Treatment harms were poorly studied and sparsely reported. Two poor-quality studies evaluated treatment of subclinical hyperthyroidism but examined intermediate outcomes. No study evaluated treatment versus no treatment of screen-detected, undiagnosed overt thyroid dysfunction.English-language articles only, no treatment study performed in the United States, and small trials with short duration that used different dosage protocols.More research is needed to determine the clinical benefits associated with thyroid screening.Agency for Healthcare Research and Quality.
Chronic Kidney Disease as a Risk Factor for Cardiovascular Disease and All-Cause Mortality
Authors: Daniel E. Weiner, Hocine Tighiouart, Manish G. Amin, Paul C. Stark, Bonnie MacLeod, John L. Griffith, Deeb N. Salem, Andrew S. Levey, Mark J. Sarnak
Journal: Journal of the American Society of Nephrology (2004)

Chronic kidney disease (CKD) is a major public health problem. Conflicting evidence exists among community-based studies as to whether CKD is an independent risk factor for adverse cardiovascular outcomes. After subjects with a baseline history of cardiovascular disease were excluded, data from four publicly available, community-based longitudinal studies were pooled: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, and Framingham Offspring Study. Serum creatinine levels were indirectly calibrated across studies. CKD was defined by a GFR between 15 and 60 ml/min per 1.73 m(2). A composite of myocardial infarction, fatal coronary heart disease, stroke, and death was the primary study outcome. Cox proportional hazards models were used to adjust for study, demographic variables, educational status, and other cardiovascular risk factors. The total population included 22,634 subjects; 18.4% of the population was black, and 7.4% had CKD. There were 3262 events. In adjusted analyses, CKD was an independent risk factor for the composite study outcome (hazard ratio [HR], 1.19; 95% confidence interval [CI], 1.07-1.32), and there was a significant interaction between kidney function and race. Black individuals with CKD had an adjusted HR of 1.76 (95% CI, 1.35-2.31), whereas whites had an adjusted HR of 1.13 (95% CI, 1.02-1.26). CKD is a risk factor for the composite outcome of all-cause mortality and cardiovascular disease in the general population and a more pronounced risk factor in blacks than in whites. It is hypothesized that this effect may be due to more frequent or more severe subclinical vascular disease secondary to hypertension or diabetes in black individuals.