tbuckley/cabot-search huggingface dataset:
Enhanced sarcolemmal Ca2+ efflux reduces sarcoplasmic reticulum Ca2+ content and systolic Ca2+ in cardiac hypertrophy
Authors: M DIAZ
Journal: Cardiovascular Research (2004)

Recent work has identified reductions in the systolic Ca(2+) transient in cardiac disease states. The aim of the present study was to identify the mechanisms responsible for perturbations of intracellular calcium homeostasis in isolated cardiac myocytes and determine if such changes can quantitatively explain the reduced systolic Ca(2+) transient.Left ventricular hypertrophy (LVH) was induced by aortic coarctation in adult ferrets. Changes in intracellular Ca(2+) regulation, sarcolemmal Ca(2+) fluxes and SR function were measured in single left ventricular cardiac myocytes.Cardiac hypertrophy was associated with a 29% increase in action potential duration (APD(90)); a 48% reduction in the amplitude of and 19% slowing in the rate of decay of the systolic Ca(2+) transient; a 20% decrease in SR Ca(2+) content and a 36% increase in inward Na(+)-Ca(2+) exchange current for a given change in [Ca(2+)](i) (all P<0.05). Peak L-type Ca(2+) current density, integrated Ca(2+) influx and SERCA2a protein levels remained unchanged in hypertrophy. By determining the relationship between SR Ca(2+) content and systolic Ca(2+), the reduction in SR Ca(2+) content quantitatively explained the smaller systolic Ca(2+) transient. The reduced SR Ca(2+) content also accounted for a smaller fractional release of Ca(2+) from the SR and lower gain of excitation contraction coupling in cardiac hypertrophy. The increased sarcolemmal-mediated Ca(2+) efflux was sufficient to explain the reduction in SR Ca(2+) content.The findings indicate that the primary mechanism underlying the smaller systolic Ca(2+) transient amplitude in cardiac hypertrophy is decreased SR Ca(2+) content occurring as a consequence of reduced SR Ca(2+)-ATPase-mediated Ca(2+) uptake and increased sarcolemmal-mediated Ca(2+) efflux from the cell. The increased Na(+)-Ca(2+) exchange-mediated current for a given change in intracellular Ca(2+) concentration provides a mechanism for the development of arrhythmias in the face of a reduced SR Ca(2+) load in cardiac hypertrophy.
T cell-dependent protective effects of CpG motifs of bacterial DNA in experimental colitis are mediated by CD11c+ dendritic cells
Authors: C. Hofmann, N. Dunger, N. Grunwald, G. J. Hammerling, P. Hoffmann, J. Scholmerich, W. Falk, F. Obermeier
Journal: Gut (2010)

<h3>Background</h3> Oligodeoxynucleotides (ODNs) containing unmethylated cytosine–guanosine (CpG) sequence motifs constitute the immunostimulatory components of bacterial DNA which potently activate innate immunity. Administration of CpG-ODNs before the onset of experimental colitis prevents intestinal inflammation by induction of colitis-suppressing T cells. <h3>Aims</h3> To identify the interplay between innate and adaptive immune cells finally leading to protective CpG-ODN effects in intestinal inflammation. <h3>Methods</h3> Total splenic cells or purified selected cell types (CD4<sup>+</sup>CD62L<sup>+</sup> T cells alone or with B cells or dendritic cells (DCs)) from BALB/c mice were (co)-incubated in vitro with CpG-ODN for 5 days and CD4<sup>+</sup>CD62L<sup>+</sup> cells were injected intraperitoneally into C.B.-17 SCID (severe combined immunodeficiency) mice. Splenic CD4<sup>+</sup>CD62L<sup>+</sup> T cells were isolated from transgenic donor mice in which CD11c<sup>+</sup> DCs were depleted by diphtheria toxin administration during CpG-ODN treatment and injected into C57BL/6 Rag2<sup>−/−</sup> recipients. Intestinal inflammation was evaluated by histological scoring and cytokine secretion of mesenteric lymph node cells. <h3>Results</h3> CpG-ODN treatment of total splenic cells but not of purified CD4<sup>+</sup>CD62L<sup>+</sup> cells reduced the colitogenic potential of transferred T cells. While CpG-ODN stimulation of co-cultured CD4<sup>+</sup>CD62L<sup>+</sup> and B-cells did not alter the colitogenic potential of T cells, co-incubation of CpG-ODN-stimulated DCs and CD4<sup>+</sup>CD62L<sup>+</sup> cells reduced the colitogenic potential of the T cell population. Depletion of CD11c<sup>+</sup> DCs during CpG-ODN administration in vivo abolished the protective CpG-ODN effects. <h3>Conclusions</h3> CpG-ODN-dependent protective effects in experimental colitis act indirectly on CD4<sup>+</sup>CD62L<sup>+</sup> T cells. While the involvement of B cells could be excluded, CD11c<sup>+</sup> DCs were identified as key mediators of CpG-ODN-induced protection in experimental colitis.
Intraoperative Red Blood Cell Transfusion During Coronary Artery Bypass Graft Surgery Increases the Risk of Postoperative Low-Output Heart Failure
Authors: Stephen D. Surgenor, Gordon R. DeFoe, Mary P. Fillinger, Donald S. Likosky, Robert C. Groom, Cantwell Clark, Robert E. Helm, Robert S. Kramer, Bruce J. Leavitt, John D. Klemperer, Charles F. Krumholz, Benjamin M. Westbrook, Dean J. Galatis, Carmine Frumiento, Cathy S. Ross, Elaine M. Olmstead, Gerald T. O’Connor
Journal: Circulation (2006)

Hemodilutional anemia during cardiopulmonary bypass (CPB) is associated with increased mortality during coronary artery bypass graft (CABG) surgery. The impact of intraoperative red blood cell (RBC) transfusion to treat anemia during surgery is less understood. We examined the relationship between anemia during CPB, RBC transfusion, and risk of low-output heart failure (LOF).Data were collected on 8004 isolated CABG patients in northern New England between 1996 and 2004. Patients were excluded if they experienced postoperative bleeding or received > or = 3 units of transfused RBCs. LOF was defined as need for intraoperative or postoperative intra-aortic balloon pump, return to CPB, or > or = 2 inotropes at 48 hours. Having a lower nadir HCT was also associated with an increased risk of developing LOF (adjusted odds ratio, 0.90; 95% CI, 0.82 to 0.92; P=0.016), and that risk was further increased when patients received RBC transfusion. When adjusted for nadir hematocrit, exposure to RBC transfusion was a significant, independent predictor of LOF (adjusted odds ratio, 1.27; 95% CI, 1.00 to 1.61; P=0.047).In this study, we observed that exposure to both hemodilutional anemia and RBC transfusion during surgery are associated with increased risk of LOF, defined as placement of an intraoperative or postoperative intra-aortic balloon pump, return to CPB after initial separation, or treatment with > or = 2 inotropes at 48 hours postoperatively, after CABG. The risk of LOF is greater among patients exposed to intraoperative RBCs versus anemia alone.
Nonalbuminuric Renal Insufficiency in Type 2 Diabetes
Authors: Richard J. MacIsaac, Con Tsalamandris, Sianna Panagiotopoulos, Trudy J. Smith, Karen J. McNeil, George Jerums
Journal: Diabetes Care (2004)

OBJECTIVE—To determine the prevalence and characteristics of patients with type 2 diabetes who have impaired renal function, defined as a glomerular filtration rate (GFR) &amp;lt;60 ml · min−1 · 1.73 m−2, and normoalbuminuria. RESEARCH DESIGN AND METHODS—A cross-sectional survey of 301 outpatients attending a single tertiary referral center using the plasma disappearance of isotopic 99mTc-diethylene-triamine-penta-acetic acid to measure GFR and at least two measurements of urinary albumin excretion rate (AER) over 24 h to determine albuminuria. RESULTS—A total of 109 patients (36%) had a GFR &amp;lt;60 ml · min−1 · 1.73 m−2. The overall prevalence of normo-, micro-, and macroalbuminuria was 43 of 109 (39%), 38 of 109 (35%), and 28 of 109 (26%), respectively. Compared with patients with macroalbuminuria, those with normoalbuminuria were more likely to be older and female. After excluding patients whose normoalbuminuric status was possibly related to the initiation of a renin-angiotensin system (RAS) inhibitor before the start of the study, the prevalence of a GFR &amp;lt;60 ml · min−1 · 1.73 m−2 and normoalbuminuria was 23%. Temporal changes in GFR in a subset of 34 of 109 (32%) unselected patients with impaired renal function were available for comparison over a 3- to 10-year period. The rates of decline in GFR (ml · min−1 · 1.73 m−2 · year−1) of −4.6 ± 1.0, −2.8 ± 1.0, and −3.0 ± 07 were not significantly different for normo- (n = 12), micro- (n = 12), and macroalbuminuric (n = 10) patients, respectively. CONCLUSIONS—These results suggest that patients with type 2 diabetes can commonly progress to a significant degree of renal impairment while remaining normoalbuminuric.
Dietary Omega-3 Fatty Acids, <i>Cyclooxygenase-2</i> Genetic Variation, and Aggressive Prostate Cancer Risk
Authors: Vincent Fradet, Iona Cheng, Graham Casey, John S. Witte
Journal: Clinical Cancer Research (2009)

Dietary intake of long-chain omega-3 (LC n-3) polyunsaturated fatty acids may reduce inflammation and in turn decrease risk of prostate cancer development and progression. This potential effect may be modified by genetic variation in cyclooxygenase-2 (COX-2), a key enzyme in fatty acid metabolism and inflammation.
Value of P-Glycoprotein and Clinicopathologic Factors as the Basis for New Treatment Strategies in High-Grade Osteosarcoma of the Extremities
Authors: Massimo Serra, Katia Scotlandi, Gemma Reverter-Branchat, Stefano Ferrari, Maria C. Manara, Stefania Benini, Marina Incaprera, Franco Bertoni, Mario Mercuri, Antonio Briccoli, Gaetano Bacci, Piero Picci
Journal: Journal of Clinical Oncology (2003)

To evaluate the prognostic value of P-glycoprotein and clinicopathologic parameters in a large series of high-grade osteosarcoma (OS) patients treated at the Rizzoli Institute.With the use of immunohistochemistry, P-glycoprotein was assessed in 149 patients with primary, nonmetastatic, high-grade OS who were homogeneously treated with chemotherapy protocols based on doxorubicin, high-dose methotrexate, and cisplatin and the addition of ifosfamide in the postoperative phase.P-glycoprotein positivity was found in 47 of 149 cases (32%) and was significantly associated with a higher incidence of relapse and a worse outcome, as was age younger than 12 years and tumor volume greater then 150 mL at diagnosis. Multivariate analysis further confirmed the prognostic value of these parameters, which all were independent adverse prognostic factors. Event-free survival and proportional hazards regression analyses confirmed that overexpression of P-glycoprotein at clinical onset is the most important adverse prognostic factor for high-grade OS patients treated with these chemotherapy protocols.Increased P-glycoprotein levels, together with tumor volume and age, should be taken into consideration to identify, at time of diagnosis, subgroups of OS patients with a higher risk of recurrence. This subgroup identification will constitute the basis for drawing individualized treatment protocols on the basis of risk evaluation, with the aim of using more aggressive chemotherapy, or combination chemotherapy with other adjuvants, only in those patients for which more aggressive regimens are strictly necessary and warranted.
Reversal of Acquired Drug Resistance in <i>FLT3</i>-Mutated Acute Myeloid Leukemia Cells via Distinct Drug Combination Strategies
Authors: Weiguo Zhang, Chen Gao, Marina Konopleva, Ye Chen, Rodrigo O. Jacamo, Gautam Borthakur, Jorge E. Cortes, Farhad Ravandi, Abhijit Ramachandran, Michael Andreeff
Journal: Clinical Cancer Research (2014)

Abstract Purpose: FMS-like tyrosine kinase-3 (FLT3) internal tandem duplication (FLT3-ITD) mutations are common in patients with acute myeloid leukemia (AML). These patients regularly develop resistance to FLT3 inhibitors suggesting that targeted combination drug strategies are needed to enhance AML therapy efficacy. Experimental Design: Acquired point mutations of FLT3-ITD gene were screened using cDNA-based sequencing approach in vitro sorafenib-resistant cells, which were developed by long-term exposure of Ba/F3-ITD to increasing doses of sorafenib, and in FLT3-ITD mutated AML patients, who developed relapse following sorafenib therapy. Drug effects (e.g., proliferation inhibition, apoptosis induction, and changes in signal transduction protein expression) were assessed in AML cells harboring the point mutations in vitro and in FLT3-ITD–mutated AML patient samples. Results: We identified several acquired point mutations in the tyrosine kinase domains (TKD) of the FLT3 gene in sorafenib-resistant murine leukemia cell line carrying human FLT3-ITD mutations, which were also detected in two of four sorafenib-resistant patient samples. Engineering these point mutations into Ba/F3-ITD cells generated sublines that demonstrated varying degrees of sorafenib [a type II tyrosine kinase inhibitor (TKI)] resistance. A similar pattern of resistance could be observed by exposing these sublines to the other type II TKIs AC220 and MLN518. However, these sublines retained sensitivity to the type I TKIs PKC412 or crenolanib. The combination of crenolanib with sorafenib demonstrated marked cytotoxic effects in all of the sorafenib-resistant sublines. Conclusions: These combination strategies could be clinically important in reversing acquired resistance to FLT3 inhibition in AML. Clin Cancer Res; 20(9); 2363–74. ©2014 AACR.
Survival in Cerebral Palsy
Authors: Peter Cohen
Journal: JAMA (1966)

Eighty-eight deaths occurred in a study group of 1,416 individuals with cerebral palsy under the age of 21 years during 8,031 person-years of follow-up. This represented an eight- to ninefold excess over expected mortality— the smallest excess being in the spastic individuals (tripling) and the largest in patients with multifocal disease and mixed deficits (18-fold increase). The relative longevity of noninstitutionalized individuals with cerebral palsy calls for long-range planning different from that which is adequate for the markedly accelerated mortality of their institutionalized counterparts.
Associations between Recent Exposure to Ambient Fine Particulate Matter and Blood Pressure in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Amy H. Auchincloss, Ana V. Diez Roux, J. Timothy Dvonch, Patrick L. Brown, R. Graham Barr, Martha L. Daviglus, David C. Goff, Joel D. Kaufman, Marie S. O’Neill
Journal: Environmental Health Perspectives (2008)

BackgroundBlood pressure (BP) may be implicated in associations observed between ambient particulate matter and cardiovascular morbidity and mortality. This study examined cross-sectional associations between short-term ambient fine particles (particulate matter ≤ 2.5 μm in aerodynamic diameter; PM2.5) and BP: systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse pressure (PP).MethodsThe study sample included 5,112 persons 45–84 years of age, free of cardiovascular disease at the Multi-Ethnic Study of Atherosclerosis baseline examination (2000–2002). Data from U.S. Environmental Protection Agency monitors were used to estimate ambient PM2.5 exposures for the preceding 1, 2, 7, 30, and 60 days. Roadway data were used to estimate local exposures to traffic-related particles.ResultsResults from linear regression found PP and SBP positively associated with PM2.5. For example, a 10-μg/m3 increase in PM2.5 30-day mean was associated with 1.12 mmHg higher pulse pressure [95% confidence interval (CI), 0.28–1.97] and 0.99 mmHg higher systolic BP (95% CI, –0.15 to 2.13), adjusted for age, sex, race/ethnicity, income, education, body mass index, diabetes, cigarette smoking and environmental tobacco smoke, alcohol use, physical activity, medications, atmospheric pressure, and temperature. Results were much weaker and not statistically significant for MAP and DBP. Although traffic-related variables were not themselves associated with BP, the association between PM2.5 and BP was stronger in the presence of higher traffic exposure.ConclusionsHigher SBP and PP were associated with ambient levels of PM2.5 and the association was stronger in the presence of roadway traffic, suggesting that impairment of blood pressure regulation may play a role in response to air pollution.
ITPR2 as a susceptibility gene in sporadic amyotrophic lateral sclerosis: a genome-wide association study
Authors: Michael A van Es, Paul W Van Vught, Hylke M Blauw, Lude Franke, Christiaan G Saris, Peter M Andersen, Ludo Van Den Bosch, Sonja W de Jong, Ruben van 't Slot, Anna Birve, Robin Lemmens, Vianney de Jong, Frank Baas, Helenius J Schelhaas, Kristel Sleegers, Christine Van Broeckhoven, John HJ Wokke, Cisca Wijmenga, Wim Robberecht, Jan H Veldink, Roel A Ophoff, Leonard H van den Berg
Journal: The Lancet Neurology (2007)
Physical Activity, Body Mass Index, and Mammographic Density in Postmenopausal Breast Cancer Survivors
Authors: Melinda L. Irwin, Erin J. Aiello, Anne McTiernan, Leslie Bernstein, Frank D. Gilliland, Richard N. Baumgartner, Kathy B. Baumgartner, Rachel Ballard-Barbash
Journal: Journal of Clinical Oncology (2007)

Purpose To investigate the association between physical activity, body mass index (BMI), and mammographic density in a racially/ethnically diverse population-based sample of 522 postmenopausal women diagnosed with stage 0-IIIA breast cancer and enrolled in the Health, Eating, Activity, and Lifestyle Study. Methods We collected information on BMI and physical activity during a clinic visit 2 to 3 years after diagnosis. Weight and height were measured in a standard manner. Using an interview-administered questionnaire, participants recalled the type, duration, and frequency of physical activities they had performed in the last year. We estimated dense area and percentage density as a continuous measure using a computer-assisted software program from mammograms imaged approximately 1 to 2 years after diagnosis. Analysis of covariance methods were used to obtain mean density across WHO BMI categories and physical activity tertiles adjusted for confounders. Results We observed a statistically significant decline in percentage density (P for trend = .0001), and mammographic dense area (P for trend = .0052), with increasing level of BMI adjusted for potential covariates. We observed a statistically significant decline in mammographic dense area (P for trend = .036) with increasing level of sports/recreational physical activity in women with a BMI of at least 30 kg/m 2 . Conversely, in women with a BMI less than 25 kg/m 2 , we observed a non–statistically significant increase in mammographic dense area and percentage density with increasing level of sports/recreational physical activity. Conclusion Increasing physical activity among obese postmenopausal breast cancer survivors may be a reasonable intervention approach to reduce mammographic density.
Endoscopy training: time to stop counting procedures?
Authors: Michael Bretthauer, Aleidis Skard Brandrud
Journal: Gut (2014)

Until recently, training of endoscopists was largely up to the local environment, often unstructured and only sporadically supervised. Consequently, there were large variations in the performance of endoscopy, and the quality of the service was very often too poor.1 During recent years, some countries have made great efforts to formalise and structure endoscopist training, often within the framework of continual quality improvement initiatives. This has led to impressive and sustained improvement in the quality of endoscopy services, as recently shown for colonoscopies in the UK.2

The number of procedures performed during training or practice has long been used as a measure of competency. Clearly, competency of technical skills is related to how often someone does something. Repetition (increasing the number of times one does something within a certain amount of time) is a well recognised tool of learning and …
Phase I Study of the Cyclin-Dependent Kinase Inhibitor Flavopiridol in Combination With Paclitaxel in Patients With Advanced Solid Tumors
Authors: Gary K. Schwartz, Eileen O’Reilly, David Ilson, Leonard Saltz, Sunil Sharma, William Tong, Peter Maslak, Maxine Stoltz, Larry Eden, Pam Perkins, Sandra Endres, John Barazzoul, David Spriggs, David Kelsen
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Preclinical studies indicate that the cyclin-dependent kinase inhibitor flavopiridol potentiates the induction of apoptosis by paclitaxel, provided paclitaxel is followed by flavopiridol. We therefore designed a phase I clinical trial of sequential paclitaxel and flavopiridol. PATIENTS AND METHODS: Paclitaxel was administered at a fixed dose, as either a 24- or 3-hour infusion on day 1, followed by a 24-hour infusion of flavopiridol on day 2. Doses of flavopiridol were escalated in successive cohorts according to a modified Fibonacci design. Flavopiridol pharmacokinetics were obtained on all patients. RESULTS: Dose-limiting neutropenia developed with 24-hour paclitaxel doses of 135 and 100 mg/m 2 and flavopiridol doses of 10 and 20 mg/m 2 , respectively. With 3-hour paclitaxel at 100 mg/m 2 , flavopiridol could be escalated to 70 mg/m 2 without dose-limiting toxicity. With 3-hour paclitaxel next escalated to 135 mg/m 2 , dose-limiting neutropenia and pulmonary toxicity occurred when flavopiridol was escalated to 94 mg/m 2 . This did not correlate with any change in flavopiridol or paclitaxel pharmacokinetics. At a 3-hour paclitaxel dose of 175 mg/m 2 , dose-limiting pulmonary toxicity occurred in only one patient at flavopiridol doses under 94 mg/m 2 . Clinical activity was observed in patients with esophagus, lung, and prostate cancer, including patients who had progressed on paclitaxel. CONCLUSION: The recommended phase II doses will be a 3-hour infusion of paclitaxel at 175 mg/m 2 on day 1 followed by a 24-hour infusion of flavopiridol at 70 mg/m 2 on day 2. Flavopiridol dose escalations to 80 mg/m 2 are possible. At these doses, toxicities are manageable and clinical activity is promising.
The ambition of the European Respiratory Journal
Authors: Marc Humbert
Journal: European Respiratory Journal (2012)

Counterculture icon Timothy Leary once said: “Women who seek to be equal with men lack ambition” [1]. As incoming Chief Editor of the European Respiratory Journal ( ERJ ), I will bluntly state that the ambition of the Journal is not to seek to be equal with other respiratory publications but to be the best possible publication available to help, inform and open new horizons to junior and established healthcare professionals and scientists who have an interest in (respiratory) medicine and science.

The ERJ is proud to be the flagship publication of the European Respiratory Society (ERS), an undisputed leading group of international clinicians and scientists [2, 3]. After 4 years’ service on the Editorial Board of previous Chief Editors Anh Tuan Dinh-Xuan and Vito Brusasco, I know that being the new Chief Editor of the Journal will be a difficult but exciting challenge [3, 4]. On this occasion, I would like to briefly share some facts and thoughts with you in this opening editorial.

Despite obvious limitations [5], it is now widely accepted that having the …