tbuckley/cabot-search huggingface dataset:
Acute Hemodynamic and Clinical Effects of Levosimendan in Patients With Severe Heart Failure
Authors: Mara T. Slawsky, Wilson S. Colucci, Stephen S. Gottlieb, Barry H. Greenberg, Ernest Haeusslein, Joshua Hare, Steven Hutchins, Carl V. Leier, Thierry H. LeJemtel, Evan Loh, John Nicklas, David Ogilby, Bramah N. Singh, William Smith
Journal: Circulation (2000)

We determined the short-term hemodynamic and clinical effects of levosimendan, a novel calcium-sensitizing agent, in patients with decompensated heart failure.One hundred forty-six patients with New York Heart Association functional class III or IV heart failure (mean left ventricular ejection fraction 21+/-1%) who had a pulmonary capillary wedge pressure >/=15 mm Hg and a cardiac index </=2.5 L x min(-1) x m(-2) were enrolled in a multicenter, double-blind, placebo-controlled study and randomized 2:1 to intravenous infusion of levosimendan or placebo. Drug infusions were uptitrated over 4 hours from an initial infusion rate of 0.1 microg x kg(-1) x min(-1) to a maximum rate of 0.4 microg x kg(-1) x min(-1) and maintained at the maximal tolerated infusion rate for an additional 2 hours. Levosimendan caused dose-dependent increases in stroke volume and cardiac index beginning with the lowest infusion rate and achieving maximal increases in stroke volume and cardiac index of 28% and 39%, respectively. Heart rate increased modestly (8%) at the maximal infusion rate and was not increased at the 2 lowest infusion rates. Levosimendan caused dose-dependent decreases in pulmonary capillary wedge, right atrial, pulmonary arterial, and mean arterial pressures. Levosimendan appeared to improve dyspnea and fatigue, as assessed by the patient and physician, and was not associated with a significant increase in adverse events.Levosimendan caused rapid dose-dependent improvement in hemodynamic function in patients with decompensated heart failure. These hemodynamic effects appeared to be accompanied by symptom improvement and were not associated with a significant increase in the number of adverse events. Levosimendan may be of value in the short-term management of patients with decompensated heart failure.
Hope and Noncurative Chemotherapies: Which Affects the Other?
Authors: Serge Daneault, Dominique Dion, Claude Sicotte, Louise Yelle, Suzanne Mongeau, Véronique Lussier, Manon Coulombe, Pierre Paillé
Journal: Journal of Clinical Oncology (2010)

From the Research Centre and theService of Hematology and Oncology,University of Montreal Hospital Centre;Departments of Family Medicine,Health Administration, and Medicine,Faculty of Medicine, University ofMontreal; Maisonneuve-RosemontHospital; School of Social Work andDepartment of Psychology, Universityof Quebec at Montreal, Montreal; andFaculty of Education, University ofSherbrooke, Sherbrooke, Quebec,Canada.Submitted October 29, 2009; acceptedJanuary 11, 2010; published onlineahead of print at www.jco.org onMarch 1, 2010.Supported by Grant No. IHP-97582from the Canadian Institutes of HealthResearch.Authors’ disclosures of potential con-ﬂicts of interest and author contribu-tions are found at the end of thisarticle.Corresponding author: Serge Daneault,MD, Unite´ des Soins Palliatifs, HoˆpitalNotre Dame, 1560 rue Sherbrooke est,Montreal, Quebec, Canada H2L 4M1;e-mail: serge.daneault.chum@ssss.gouv.qc.ca.© 2010 by American Society of ClinicalOncology0732-183X/10/2813-2310/$20.00DOI: 10.1200/JCO.2009.26.8425
αv Integrins Lead the Way for Colorectal Metastases
Authors: Joseph H. McCarty
Journal: Clinical Cancer Research (2008)

Abstract In this issue of Clinical Cancer Research, Conti et al. identify a crucial cell adhesion and signaling axis that promotes the proliferation, survival, and drug-resistant properties of metastatic colorectal cancer cells in the liver. The components of this pathway may be effective targets for therapeutically treating established metastatic tumors in patients with colorectal adenocarcinomas.
Equivalent generator properties of acute ischemic lesions in the isolated rabbit heart.
Authors: D M Mirvis, F W Keller, R E Ideker, D G Zettergren, R F Dowdie
Journal: Circulation Research (1978)

Equivalent generator properties of the electrical field produced by ischemic myocardium were studied in 25 isolated rabbit heart preparations.Electrocardiograms from 32 electrodes deployed about a spherical tank containing the isolated, perfused heart were recorded before and after suture ligation of the left anterior descending artery.The ligation was high (10 preparations) or low (10 preparations) along the interventricular septum.In a final five hearts, ligatures were placed sequentially in both positions.Signals were processed to quantitate the percentage of summed square (SSQ) potential attributable to a centric dipole (CD), to a four-element centric multipole series (CMS) and to a single moving dipole (SMD) during the S-T segment.Fifteen minutes after low ligation, 74 ± 12%, 98 ± 1%, and 96 ± 3% (mean ± 1 SD) of SSQ potential recorded 10 msec into the S-T segment could be accounted for by the CD, CMS, and SMD models, respectively.The computed SMD was determined to be fixed in location and orientation throughout the S-T segment but to increase in magnitude from early to late S-T.Dipole moment directly correlated with the area of the epicardial lesion (r = 0.82).Results were quantitatively similar after high ligation and after each of the sequential occlusions.Tank surface isopotential maps during the S-T segment uniformly demonstrated a single maximum that was spatially aligned with the ischemic lesion, and with an intensity proportional to both computed dipole moment and epicardial lesion size (r = 0.97).Thus, CMS and SMD cardiac models provide quantitatively accurate descriptions of the experimentally induced electrical fields.
Gentamicin Inhibits Renal Protein and Phospholipid Metabolism in Rats
Authors: DAVID P. SUNDIN, RUBEN SANDOVAL, BRUCE A. MOLITORIS
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Studies were undertaken to characterize the mechanism of aminoglycoside-induced nephrotoxicity. Early time points in gentamicin treatment (1 to 3 d) were used to investigate the development of toxic events without the complication of gross morphologic cellular alterations. Enzyme activities of cortical homogenates and brush border membrane (BBM) preparations documented little effect on specific activities or the ability to isolate representative membrane fractions. In vivo protein synthesis experiments demonstrated that gentamicin reduced cellular protein synthesis after 2 d of treatment. This inhibition increased to 50% on the third day. Total cellular proteins synthesis was inhibited to the same extent as BBM protein synthesis. However, gentamicin had different effects on homogenate versus BBM phospholipids. The total phospholipid contents in cortical homogenates and BBM from treated animals were increased, compared with control animals. A significant decrease in phospholipid synthesis was observed only in homogenates from treated animals. When effects on individual phospholipids were investigated, only an increase in phosphatidylinositol levels was observed in cortical homogenates from treated rats. However, gentamicin treatment was demonstrated to increase the levels of phosphatidylinositol and phosphatidylcholine, while decreasing the level of sphingomyelin (SPH), in BBM. Incorporation of 32 P into SPH, phosphatidylserine, and phosphatidylethanolamine was inhibited in cortical homogenates from gentamicin-treated animals; among BBM phospholipids, however, a significant decrease was observed only for SPH synthesis. It was concluded that inhibition of phospholipid degradation was quantitatively the major contributor to the effects of gentamicin on phospholipid metabolism. Confocal microscopic studies, using tracer amounts of fluorescently labeled gentamicin, revealed gentamicin in large, mostly basal structures. Correlative electron microscopic studies, using photo-oxidation techniques, demonstrated that these structures consisted of lysosomal, Golgi complex, and mitochondrial structures. These observations suggest retrograde trafficking of gentamicin and indicate a general mechanism of gentamicin-induced nephrotoxicity.
Physical and functional association of p56lck with Fc gamma RIIIA (CD16) in natural killer cells.
Authors: T W Salcedo, T Kurosaki, P Kanakaraj, J V Ravetch, B Perussia
Journal: The Journal of Experimental Medicine (1993)

The transmembrane receptor for immunoglobulin G immune complexes on natural killer (NK) cells and macrophages, Fc gamma RIIIA (CD16), mediates cellular activation through a tyrosine kinase-dependent pathway. We show that Fc gamma RIII crosslinking results in activation of the src-related kinase p56lck in NK cells and demonstrate a physical association of p56lck with Fc gamma RIIIA in immunoprecipitates from NK cells obtained using anti-Fc gamma RIII antibodies or immune complexes. Our studies show that the zeta chain, the signal transducing subunit of Fc gamma RIIIA and of T cell receptor, associates with p56lck and, in NK cells, is a substrate for this kinase. Such direct association of p56lck with the zeta subunit as confirmed by demonstrating the interaction in heterologous cells transfected with cDNA expressing p56lck and zeta. Our findings demonstrate both functional and physical association of p56lck with Fc gamma RIIIA, through direct interaction of the kinase with the zeta and/or the gamma signal transducer subunits of the receptor. These data suggest a possible mechanism by which activation via Fc gamma RIIIA occurs.
DetectiV: visualization, normalization and significance testing for pathogen-detection microarray data
Authors: Michael Watson, Juliet Dukes, Abu-Bakr Abu-Median, Donald P King, Paul Britton
Journal: Genome biology (2007)

DNA microarrays offer the possibility of testing for the presence of thousands of micro-organisms in a single experiment. However, there is a lack of reliable bioinformatics tools for the analysis of such data. We have developed DetectiV, a package for the statistical software R. DetectiV offers powerful yet simple visualization, normalization and significance testing tools. We show that DetectiV performs better than previously published software on a large, publicly available dataset.
FTY720 stimulates multidrug transporter– and cysteinyl leukotriene–dependent T cell chemotaxis to lymph nodes
Authors: Shaun M. Honig, Shuang Fu, Xia Mao, Adam Yopp, Michael D. Gunn, Gwendalyn J. Randolph, Jonathan S. Bromberg
Journal: Journal of Clinical Investigation (2003)

FTY720 is a sphingosine-derived immunosuppressant. Phosphorylated FTY720 promotes T cell homing from spleen and peripheral blood to LNs by acting as an agonist for sphingosine-1-phosphate (S1P) receptors. Here we demonstrate that FTY720 enhances the activity of the sphingosine transporter Abcb1 (Mdr1) and the leukotriene C4 transporter Abcc1 (Mrp1). Both transporters must be active for FTY720-mediated T cell migration and LN homing. Migration and homing driven by FTY720, phosphorylated FTY720, or S1P also require 5-lipoxygenase–mediated synthesis of cysteinyl leukotrienes and their efflux from the cell. FTY720-mediated LN homing events further downstream are dependent on CCL19, CCL21, VLA-4α, and CD44. Use of T cells deficient in 5-lipoxygenase, Abcb1, and Abcc1, and comparison of the effects of FTY720 with those of S1P, suggest a model of sequential engagement of Abcb1, SP1 receptors, 5-lipoxygenase, and Abcc1 to enhance T cell migration and homing.
Number needed to treat in COPD: exacerbations versus pneumonias
Authors: Samy Suissa
Journal: Thorax (2012)

<h3>Background</h3> Several recent trials in chronic obstructive pulmonary disease (COPD) have assessed the effectiveness of the fluticasone–salmeterol combination inhaler in preventing COPD exacerbations, while finding an increased risk of pneumonia. The number needed to treat (NNT) is a simple measure to perform the comparative benefit–risk impact, but its calculation involving repeated outcome events such as COPD exacerbations has been incorrect. We describe the proper methods to calculate the NNT and, using data from published trials, apply them to evaluate the relative impact of fluticasone–salmeterol treatment on exacerbations and pneumonias in patients with COPD. <h3>Methods</h3> We review the fundamental definition of NNT and quantify it for situations with varying follow-up times. We review the 'event-based' NNT, proposed and used for repeated event outcomes, show its inaccuracy, describe its proper use and provide an approximate formula for its application. <h3>Results</h3> We show that a 1-year trial of the fluticasone–salmeterol combination versus salmeterol used the incorrect event-based approach to calculate the NNT as two patients that need to be treated for 1 year to prevent one COPD exacerbation, when the proper calculation results in a NNT of 14. In contrast, 20 patients need to be treated to induce one pneumonia case. For the TORCH trial, the NNT is 44 patients treated for 3 years with fluticasone–salmeterol versus salmeterol to prevent one exacerbation compared with 16 patients to induce one pneumonia case. <h3>Conclusions</h3> The NNT is a useful measure of the effect of drugs, but its proper calculation is essential to prevent misleading clinical practice guidelines.
First-line treatment of advanced ovarian cancer with paclitaxel/carboplatin with or without epirubicin (TEC versus TC)—a gynecologic cancer intergroup study of the NSGO, EORTC GCG and NCIC CTG
Authors: K. Lindemann, R.D. Christensen, I. Vergote, G. Stuart, M.A. Izquierdo, J. Kærn, H. Havsteen, E. Eisenhauer, M. Ridderheim, A.B. Lopez, H. Hirte, E. Aavall-Lundquvist, E. Vrdoljak, J. Green, G.B. Kristensen
Journal: Annals of Oncology (2012)
Muscle Weakness and Foot Deformities in Diabetes
Authors: Carine H.M. van Schie, Cristiana Vermigli, Anne L. Carrington, Andrew Boulton
Journal: Diabetes Care (2004)

OBJECTIVE—To examine the relationships among muscle weakness, foot deformities, and peroneal and tibial nerve conduction velocity in diabetic and nondiabetic men. RESEARCH DESIGN AND METHODS—A neuropathic and foot evaluation was undertaken in 10 nondiabetic control subjects (group C) and in 36 consecutive diabetic patients attending Diabetes Centre clinics, including 10 diabetic control subjects (group D), 15 diabetic neuropathic patients (group DN), and 11 diabetic patients with a history of ulceration (group DU). Neuropathy was defined as a peroneal motor nerve conduction &amp;lt;40 m/s. Muscle weakness was assessed in seven intrinsic and seven extrinsic muscles of the foot using a semiquantitative score (max score per muscle = 3). Foot deformities were assessed using a foot deformity score (max score = 3). A higher score indicated increased muscle weakness or more severe foot deformities. Muscle weakness and foot deformities were assessed without prior knowledge of patient and neuropathy status. RESULTS—Peroneal and tibial nerve conduction velocity were associated with weakness in muscles innervated by, respectively, the peroneal and tibial nerve (r = −0.70 and r = −0.51, P &amp;lt; 0.01) and foot deformities (r = −0.60 and r = −0.59, P &amp;lt; 0.001). The DN and DU groups had more weakness in intrinsic and extrinsic muscles compared with the C and D groups. Muscles innervated by the tibial nerve had a greater proportional muscle weakness than those innervated by the peroneal nerve in the DN and DU groups. The DN and DU patients had more foot deformities (median food deformity score [interquartile range]) (3 [2–3] and 2 [2–3]) compared with D and C patients (0 [0–0.75] and 0 [0–0]). CONCLUSIONS—Important relationships have been shown between motor nerve conduction deficit and muscle weakness; however, it is still not clear whether abnormal nerve function, leading to a decrease in muscle strength, could be responsible for the development of foot deformities.
Sirt1 activation protects the mouse renal medulla from oxidative injury
Authors: Wenjuan He, Yingying Wang, Ming-Zhi Zhang, Li You, Linda S. Davis, Hong Fan, Hai-Chun Yang, Agnes B. Fogo, Roy Zent, Raymond C. Harris, Matthew D. Breyer, Chuan-Ming Hao
Journal: Journal of Clinical Investigation (2010)

Sirtuin 1 (Sirt1) is a NAD+-dependent deacetylase that exerts many of the pleiotropic effects of oxidative metabolism. Due to local hypoxia and hypertonicity, the renal medulla is subject to extreme oxidative stress. Here, we set out to investigate the role of Sirt1 in the kidney. Our initial analysis indicated that it was abundantly expressed in mouse renal medullary interstitial cells in vivo. Knocking down Sirt1 expression in primary mouse renal medullary interstitial cells substantially reduced cellular resistance to oxidative stress, while pharmacologic Sirt1 activation using either resveratrol or SRT2183 improved cell survival in response to oxidative stress. The unilateral ureteral obstruction (UUO) model of kidney injury induced markedly more renal apoptosis and fibrosis in Sirt1+/- mice than in wild-type controls, while pharmacologic Sirt1 activation substantially attenuated apoptosis and fibrosis in wild-type mice. Moreover, Sirt1 deficiency attenuated oxidative stress-induced COX2 expression in cultured mouse renal medullary interstitial cells, and Sirt1+/- mice displayed reduced UUO-induced COX2 expression in vivo. Conversely, Sirt1 activation increased renal medullary interstitial cell COX2 expression both in vitro and in vivo. Furthermore, exogenous PGE2 markedly reduced apoptosis in Sirt1-deficient renal medullary interstitial cells following oxidative stress. Taken together, these results identify Sirt1 as an important protective factor for mouse renal medullary interstitial cells following oxidative stress and suggest that the protective function of Sirt1 is partly attributable to its regulation of COX2 induction. We therefore suggest that Sirt1 provides a potential therapeutic target to minimize renal medullary cell damage following oxidative stress.
Human Tissues Contain CD141hi Cross-Presenting Dendritic Cells with Functional Homology to Mouse CD103+ Nonlymphoid Dendritic Cells
Authors: Muzlifah Haniffa, Amanda Shin, Venetia Bigley, Naomi McGovern, Pearline Teo, Peter See, Pavandip Singh Wasan, Xiao-Nong Wang, Frano Malinarich, Benoit Malleret, Anis Larbi, Pearlie Tan, Helen Zhao, Michael Poidinger, Sarah Pagan, Sharon Cookson, Rachel Dickinson, Ian Dimmick, Ruth F. Jarrett, Laurent Renia, John Tam, Colin Song, John Connolly, Jerry K.Y. Chan, Adam Gehring, Antonio Bertoletti, Matthew Collin, Florent Ginhoux
Journal: Immunity (2012)

Dendritic cell (DC)-mediated cross-presentation of exogenous antigens acquired in the periphery is critical for the initiation of CD8(+) T cell responses. Several DC subsets are described in human tissues but migratory cross-presenting DCs have not been isolated, despite their potential importance in immunity to pathogens, vaccines, and tumors and tolerance to self. Here, we identified a CD141(hi) DC present in human interstitial dermis, liver, and lung that was distinct from the majority of CD1c(+) and CD14(+) tissue DCs and superior at cross-presenting soluble antigens. Cutaneous CD141(hi) DCs were closely related to blood CD141(+) DCs, and migratory counterparts were found among skin-draining lymph node DCs. Comparative transcriptomic analysis with mouse showed tissue DC subsets to be conserved between species and permitted close alignment of human and mouse DC subsets. These studies inform the rational design of targeted immunotherapies and facilitate translation of mouse functional DC biology to the human setting.
Toll-like receptor-4 mediates obesity-induced non-alcoholic steatohepatitis through activation of X-box binding protein-1 in mice
Authors: Dewei Ye, Francois Y L Li, Karen S L Lam, Huating Li, Weiping Jia, Yu Wang, Kwan Man, Chung Mau Lo, Xiaokun Li, Aimin Xu
Journal: Gut (2012)

<h3>Background</h3> Non-alcoholic fatty liver disease is an obesity-related chronic liver disorder ranging from simple steatosis to non-alcoholic steatohepatitis (NASH), which may progress to liver fibrosis and cirrhosis. <h3>Objective</h3> Tto investigate the role of Toll-like receptor (TLR) 4 in mediating the transition from steatosis to inflammation. <h3>Methods</h3> ApoE<sup>−/−</sup>/TLR4<sup>mut</sup> mice and ApoE<sup>−/−</sup>/TLR4 wild-type mice (ApoE<sup>−/−</sup>/TLR4-WT) were generated by cross-breeding an ApoE-deficient (ApoE<sup>−/−</sup>) strain with TLR4-mutant (TLR4<sup>mut</sup>) mice, which were fed with high-fat, high-cholesterol (HFHC) diet to induce obesity. <h3>Results</h3> ApoE<sup>−/−</sup>/TLR4-WT mice fed with an HFHC diet for 12 weeks developed typical pathological features of NASH, which is associated with obesity and the metabolic syndrome. By contrast, ApoE<sup>−/−</sup>/TLR4<sup>mut</sup> mice lacking functional TLR4 were resistant to HFHC diet-induced liver inflammation and injury and were less susceptible to the diet-induced production of reactive oxygen species (ROS) and proinflammatory cytokines. In ApoE<sup>−/−</sup>/TLR4-WT mice, X-box binding protein-1 (XBP-1), a transcription factor involved in the unfolded protein responses, was activated in the liver by an HFHC diet, whereas XBP-1 activation was abrogated in ApoE<sup>−/−</sup>/TLR4<sup>mut</sup> mice. In primary rat Kupffer cells, endotoxin induced XBP-1 activation through ROS production, whereas siRNA-mediated knockdown of XBP-1 expression resulted in a marked attenuation in endotoxin-evoked NF-κB activation and cytokine production. Furthermore, adenovirus-mediated expression of dominant negative XBP-1 led to a significant attenuation in HFHC diet-induced liver inflammation and injury in mice. <h3>Conclusions</h3> These findings support the key role of TLR4 in Kupffer cells in mediating the progression of simple steatosis to NASH, by inducing ROS-dependent activation of XBP-1.
The treatment of severe falciparum malaria.
Authors: W Peters, A P Hall
Journal: BMJ (1985)

<h3>ABSTRACT</h3> <h3>Objective</h3> Renal resistive index (RRI) and renal pulsatility index (RPI) are Doppler-based variables proposed to assess renal perfusion at the bedside in critically ill patients. This study aimed to assess the accuracy of such variables to predict acute kidney injury (AKI) in mechanically ventilated children. <h3>Design</h3> Prospective single-center observational study <h3>Setting</h3> Pediatric intensive care unit of a quaternary care teaching hospital. <h3>Patients</h3> 84 children under controlled ventilation (median age of 5.1 months and weight of 6.6 kg). <h3>Interventions</h3> Consecutive children underwent renal Doppler ultrasound examination within 24 hours of invasive mechanical ventilation. Renal resistive index (RRI) and renal pulsatility index (RPI) were measured. The primary outcome was severe AKI (KDIGO stage 2 or 3) on day 3. Secondary outcomes included the persistence of severe AKI on day 5. <h3>Results</h3> On day 3, 22 patients were classified as having AKI (any stage), of which 12 were severe. RRI could effectively predict severe AKI (area under the ROC curve [AUC] 0.94; 95% CI 0.86 – 0.98; <i>p</i> &lt; 0.001) as well as RPI (AUC 0.86; 95% CI 0.76 – 0.92; <i>p</i> &lt; 0.001). The AUC of the IRR was significantly greater than that obtained from the RPI (<i>p</i> = 0.023). The optimal cutoff for RRI was 0.85 (sensitivity, 91.7%; specificity, 84.7%; positive predictive value, 50.0%; and negative predictive value 98.4%). Similar results were obtained when the accuracy to predict AKI on day 5 was assessed. Significant correlations were observed between RRI and estimated glomerular filtration rate at enrollment (ρ = -0.495, <i>p</i>&lt;0.001) and on day 3 (ρ = -0.467, <i>p</i> &lt;0.001). <h3>Conclusions</h3> Renal Doppler ultrasound may be a promising tool to predict AKI in critically ill children under invasive mechanical ventilation.