tbuckley/cabot-search huggingface dataset:
Abstract 18116: The Effect of Therapeutic Hypothermia on QT and Corrected QT Intervals in Patients With Cardiac Arrest and Their Association With Malignant Arrhythmias
Authors: David F Miranda, Yader Sandoval, Zachary P Rosol, Stephen W Smith, Bradley A Bart, Steven R Goldsmith
Journal: Circulation (2014)

Background: Therapeutic hypothermia (TH) is used to improve neurological outcomes after cardiac arrest. The effects of TH on manually and computer derived measures of the QT and corrected QT (QTc) intervals, and their association with malignant arrhythmias, have not been well characterized. Methods: We performed a retrospective study of 193 patients undergoing TH for cardiac arrest between July 2007 and February 2013, reviewing 12-lead electrocardiograms before, during and after TH if available. We tabulated both manually-calculated and computer-derived QT and QTc intervals and examined the relationship between QTc and the occurrence of malignant arrhythmias, as well as the influence of ejection fraction (EF), serum electrolytes and any known QT-prolonging medications. Results: 193 patients underwent TH for cardiac arrest, among which 100% (n=193) had a pre-TH ECG; 87% (n=167) had an ECG during-TH, and 74% (n=142) had a post-TH ECG. Computerized QTc was significantly different than manually derived QTc at...
Affinity of Cystathionine β-Synthase for Pyridoxal 5′-Phosphate in Cultured Cells
Authors: Mark H. Lipson, Jan Kraus, Leon E. Rosenberg
Journal: Journal of Clinical Investigation (1980)

Previous attempts to correlate in vivo pyridoxine-responsiveness with in vitro assays of cystathionine β-synthase activity in synthase-deficient homocystinuric patients have been only partially successful. All such studies, however, have been conducted with extracts of cultured skin fibroblasts grown in medium containing a high concentration (1,000 ng/ml) of pyridoxal. Having recently shown that such growth conditions may obscure important aspects of enzyme-coenzyme interactions by saturating most synthase molecules with their cofactor, pyridoxal 5′-phosphate, we have established conditions for growth of cells in pyridoxal-free medium. Under these conditions, intracellular pyridoxal 5′-phosphate fell by >95%, and saturation of cystathionine β-synthase apoenzyme with pyridoxal 5′-phosphate decreased from a predepletion value of 70% to <10%. When such depleted cells were grown in media containing pyridoxal concentrations ranging from 0 to 1,000 ng/ml, cellular pyridoxal 5′-phosphate reached a maximum of 30 ng/mg cell protein at a medium pyridoxal concentration of 100 ng/ml. Maximal saturation of aposynthase with coenzyme in control cells was reached at a medium pyridoxal concentration of 10 ng/ml. In contrast, maximal saturation of residual aposynthase in cells from an in vivo responsive patient was achieved at a medium pyridoxal concentration of 25-50 ng/ml, whereas that from cells from an in vivo unresponsive patient was reached at 100 ng/ml. Estimates of the affinity of control and mutant cystathionine β-synthase for pyridoxal 5′-phosphate in cell extracts supported the differences observed in intact cells. The apparent Km of cystathionine β-synthase for pyridoxal 5′-phosphate in extracts of depleted cells from four in vivo-responsive patients was two to four times that of control. In contrast, the Km for pyridoxal 5′-phosphate in two lines from in vivo nonresponsive patients was 16- and 63-fold normal. These results suggest that cystathionine β-synthase activity in cells from patients containing a mutant enzyme with a moderately reduced affinity for pyridoxal 5′-phosphate can be increased by pyridoxine supplements in vivo, whereas that from patients whose enzyme has a more dramatically reduced affinity for the coenzyme cannot be so modulated because of limits on the capacity of such cells to accumulate and retain pyridoxal 5′-phosphate.
663. Genetic Re-Targeting of Adenovirus Using a Hyperstable scFv Domain and an Affibody® Molecule Against Her2/neu
Authors: Leif Lindholm, Karin Andersson, Pierre Boulanger, Karolin Frykholm, Petra Henning, Rob Hoeben, Saw See Hong, Jenny Johannisson, Maria Magnusson, Susanna Myhre, Per-Åke Nygren, Elisabeth Pettersson, Stefan Ståhl, Jort Vellinga, Maria Wikman
Journal: Molecular Therapy (2004)

One important goal in gene therapy is to develop adenovirus (Ad) vectors that are genetically de-targeted as well as re-targeted. Genetic re-targeting of Ad using complex cell-binding ligands has previously not been possible. We have previously demonstrated that ligands for genetic re-targeting of adenoviruses must be able to fold correctly in the cytoplasm of virus producing cells, a milieu that is not conducive to the formation of disulphide bonds.
Abstract 4401: Two Independent Genetic Variants in NOS1AP are Associated with QT interval in a Multi-Ethnic Population: the Dallas Heart Study
Authors: Dan E Arking, Amit Khera, Chao Xing, Wen H Kao, Aravinda Chakravarti
Journal: Circulation (2008)

Extremes of QT interval are associated with increased risk for sudden cardiac death (SCD), and thus identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous work revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We thus sought to characterize the effects of NOS1AP genetic variants in the multi-ethnic population-based Dallas Heart Study (DHS). Among 3,557 participants in DHS with available DNA, those without QT interval, heart rate, age, and/or sex information, and those with QRS &gt;120 or undetermined ethnicity were excluded, resulting in 2,949 samples available for analysis (501 Hispanic, 1,506 Black, 942 White). Sex- and ethnicity-stratified linear regression was used to correct QT interval for heart rate and age. Eight SNPs spanning the region previously associated with QT interval were genotyped, and ethnic-specific analyses were performed under an additive genetic model. The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in the White participants (+2.6 ms, P&lt;0.005) as well as in Blacks (+3.2 ms, P&lt;3.6 × 10 –5), with the same direction of effect in Hispanics (+1.5 ms, P&lt;0.17). A second SNP, rs16856785, which was uncorrelated with rs16847548 (r2 &lt; 0.01 in Blacks) was also associated with QT interval in Blacks (+1.6 ms, P&lt;0.01), with qualitatively similar results in Whites (+0.9 ms, P&lt;0.33) and Hispanics (+0.6 ms, P&lt;0.66). Adjusting for local and global ancestry using Ancestry Informative Markers did not significantly alter the results. Comparing Blacks homozygous at both SNPs for the QT lengthening allele to Blacks homozygous for the complementary alleles revealed a 13.9 ms difference in QT interval. These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends in Hispanics. Further, a second, independent site within NOS1AP has been implicated in modulating QT interval, highlighting the importance of NOS1AP genetic variants in regulating QT interval.
Short Sleep Duration and Incident Coronary Artery Calcification
Authors: Christopher Ryan King, Kristen L. Knutson, Paul J. Rathouz, Steve Sidney, Kiang Liu, Diane S. Lauderdale
Journal: JAMA (2008)

Coronary artery calcification is a subclinical predictor of coronary heart disease. Recent studies have found that sleep duration is correlated with established risk factors for calcification including glucose regulation, blood pressure, sex, age, education, and body mass index.To determine whether objective and subjective measures of sleep duration and quality are associated with incidence of calcification over 5 years and whether calcification risk factors mediate the association.Observational cohort of home monitoring in a healthy middle-aged population of 495 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort Chicago site (black and white men and women aged 35-47 years at year 15 of the study in 2000-2001 with follow-up data at year 20 in 2005-2006). Potential confounders (age, sex, race, education, apnea risk, smoking status) and mediators (lipids, blood pressure, body mass index, diabetes, inflammatory markers, alcohol consumption, depression, hostility, self-reported medical conditions) were measured at both baseline and follow-up. Sleep metrics (wrist actigraphy measured duration and fragmentation, daytime sleepiness, overall quality, self-reported duration) were examined for association with incident calcification. Participants had no detectable calcification at baseline.Coronary artery calcification was measured by computed tomography in 2000-2001 and 2005-2006 and incidence of new calcification over that time was the primary outcome.Five-year calcification incidence was 12.3% (n = 61). Longer measured sleep duration was significantly associated with reduced calcification incidence (adjusted odds ratio, 0.67 per hour [95% confidence interval, 0.49-0.91 per hour]; P = .01). No potential mediators appreciably altered the magnitude or significance of sleep (adjusted odds ratio estimates ranged from 0.64 to 0.68 per sleep hour; maximum P = .02). Alternative sleep metrics were not significantly associated with calcification.Longer measured sleep is associated with lower calcification incidence independent of examined potential mediators and confounders.
Toronto doctor convicted of assisting suicide
Authors: David Spurgeon
Journal: BMJ (1998)

A Toronto doctor, the first in North America to be convicted of assisting suicide, has been sentenced to jail but was released on bail to await the outcome of an appeal.

Dr Maurice Genereux, who admitted prescribing lethal doses of a barbiturate to two healthy but depressed men with HIV infection, was sentenced to two years less a day, followed by three years on probation. His sentence is …
Abstract 18240: Septal Pacing Improves Prognosis in Patients with High Pacemaker Dependency: A Propensity-matched Analysis
Authors: Akira Mizukami, Yuya Matsue, Yoshihisa Naruse, Shinya Kowase, Kenji Kurosaki, Makoto Suzuki, Akihiko Matsumura, Akihiko Nogami, Kazutaka Aonuma, Yuji Hashimoto
Journal: Circulation (2014)

Background: The effect of septal pacing as opposed to apical pacing on prognosis in patients undergoing pacemaker implantation still remains controversial. Methods: A total of 685 patients who have received their first pacemaker implantation from year 2008 to 2013 at 2 centers in Japan (50.4% male, age 75.3±10.6 years, 33.3% septal pacing) were analyzed. The primary endpoint was combined endpoint of all cause death and hospitalization due to heart failure, and the median follow-up period was 795 days (interquartile range, 407-1369 days). A propensity-matched analysis successfully matched 438 patients into two groups (septal pacing and apical pacing groups) resulting in 219 patients in each group with well-balanced baseline characteristics. Results: The primary endpoint was observed in 63 patients (14.4%) in the matched cohort with marginal improvement of prognosis in septal pacing group (hazard ratio (HR), 0.52; 95% confidence interval (CI), 0.27-1.02; P=0.056). In subgroup analysis, significant interacti...
Interleukin‐6 Receptor Blockade Enhances CD39+ Regulatory T Cell Development in Rheumatoid Arthritis and in Experimental Arthritis
Authors: A. Thiolat, L. Semerano, Y. M. Pers, J. Biton, D. Lemeiter, P. Portales, J. Quentin, C. Jorgensen, P. Decker, M.‐C. Boissier, P. Louis‐Plence, N. Bessis
Journal: Arthritis & Rheumatology (2013)

The rationale for blocking interleukin-6 (IL-6) in rheumatoid arthritis (RA) lies chiefly in the proinflammatory effect of this cytokine. Few studies have evaluated the consequences of anti-IL-6 receptor (IL-6R) antibody treatment on Treg cells. This study was undertaken to elucidate the mechanism of action of anti-IL-6R antibody treatment by studying the effects on Treg cells in an experimental arthritis model and in patients with RA.Mice with collagen-induced arthritis (CIA) were treated with a mouse anti-IL-6R antibody (MR16-1), and changes in Treg, Th1, and Th17 cells were assessed at key time points during the course of the disease. Peripheral blood from 15 RA patients was collected on day 0 and after 3 months of tocilizumab treatment for flow cytometry analysis of Th17 and Treg cells.In MR16-1-treated mice, Th17 cell frequencies were unchanged, whereas Treg cell frequencies were increased. The Treg cell phenotype showed marked changes, with an increase in the frequency of CD39+ Treg cells in the lymph nodes and spleen. Interestingly, similar CD39+ Treg cell expansion was observed in RA patients who were tocilizumab responders at 3 months, with no change in Th17 cell frequency. Moreover, fluorescence-activated cell-sorted CD39+ Treg cells from responder RA patients were functionally able to suppress the proliferation of conventional T cells.In both CIA and RA, the frequency of functionally suppressive CD39+ Treg cells is increased as a result of anti-IL-6R treatment, whereas Th17 cells are unaffected. The modification of Treg cell frequency and phenotype may be one of the mechanisms involved in the therapeutic effect of IL-6 blockade in RA.
Abstract MP44: Assessment and Comparison of Six minute Walk Distance in Patients Undergoing Pharmacological Stress Test
Authors: Azhar A Supariwala, Seth Uretsky, Randy Cohen, Yathin Thammaiah, Swathi Sangli, Amit Correa, Manideep Duttuluri, Sai Sreenija Dukkipati, Kelly Price, Irtaza Khan, Farooq A Chaudhry, Alan Rozanski
Journal: Circulation (2014)

Background: Stress testing is widely used for diagnosis, risk stratification and prognosis of patients (pts). Although a normal stress study identifies pts at low risk, compared to exercise stress (Ex), those undergoing pharmacological stress test (PST) are at a higher risk of mortality. We studied the feasibility of a six minute walk test (SMWT) and compared the six-minute walk distance (SMWD) among Ex and PST. Methods: 328 consecutive patients [Ex=186 (57%); PST= 142 (43%)] referred for stress testing at our hospital were enrolled. Demographic and clinical information was collected. Each patient underwent a SMWT according to American Thoracic Society guidelines. Results: Patients in PST were older (62±14 vs. 57±12; p=0.001), had a higher BMI (36±30 vs. 29±6; p0.01), diabetes (46% vs. 25%; p&lt;0.001) and hyperlipidemia (55% vs. 38%; p=0.01). We found a low SMWD achieved in PST (209 m ± 131) vs. Ex (366 m ± 107; p&lt;0.001). When compared to age-gender matched healthy volunteer data, we found a significantly lower predicted SMWD in all patients suspected of CAD, with the lowest predicted SMWD in PST. (Figure) On multivariate analyses, patients undergoing PST had the highest risk (HR=10.1) of achieving lowest tertile of percent predicted SMWD, followed by female gender (HR=2.0), history of CHF, higher BMI. Only patients above 80 yrs of age had significant higher likelihood of undergoing pharmacological stress mode (OR = 7.2; 95CI =1.7 - 30.1; p=0.008). After including the interaction term for age and pharmacological stress mode, low SMWD among PST was seen in both older and young patients (p for interaction=0.46). Conclusion: SMWT is feasible in patients referred for PST. Patients with known or suspected CAD achieve a low percent predicted SMWD. This is the first study to show objective evidence of deconditioning in PST irrespective of co-morbidities. Future studies are needed to evaluate the prognostic significance of SMWT in patients undergoing pharmacological stress test.
Different expression of KCa and KATP channel and relationship to tumor permeability in syngeneic and non-syngeneic rat model
Authors: Dali Yin, John M. Ong, Bindu Konda, Jennifer-Ann Bayan, Jinwei Hu, Xiao Wang, Manuel R. Sacapano, Ksenia Prosolovich, Andres J. Espinoza, Keith L. Black
Journal: Cancer Research (2006)

4630   The blood-brain tumor barrier (BTB) significantly limits the delivery of therapeutic drugs to brain tumors. In this study, we investigated the effect of bradykinin, minoxidil sulfate and KCO912 on tumor permeability in syngeneic and non-syngeneic rat models, and the expression of bradykinin 2 (B2) receptor, K Ca  channel and K ATP  channel in the tumors of these two different models. Tumor permeability in 9L tumor-implanted Fischer or Wistar rats was determined by measuring the uptake of [ 14 C]-sucrose. Expression of B2 receptor, K Ca  channel or K ATP  channels was assayed by immunostaining and Western blot analysis. Intravenous infusion of bradykinin selectively increase the transport of [ 14 C]-sucrose to 9L tumors significantly in Fischer (17.81 ± 1.15 μg/kgmin) and Wistar (12.54 ± 1.50 μg/kgmin) rats as compared with their respective PBS-treated controls (Fischer, 7.88 ± 0.70 μg/kgmin; Wistar, 6.42 ± 0.42 μg/kgmin). Intravenous infusion of minoxidil sulfate or KCO912 significantly increase tumor permeability in Wistar rats with 9L tumors (11.72 ± 0.90 μg/kgmin, 10.86 ± 1.98 μg/kgmin respectively) when compared with controls, but not in Fischer rats. Immunostaining and Western blot analysis revealed that 9L tumor cells express B2 receptor, K Ca  channel and K ATP  channel in vitro. After implantation, B2 receptor and K Ca  channel were found in 9L tumor of Fischer and Wistar rats. However, a higher level of K ATP  channel expression was found in 9L tumors of Wistar rats than that of Fischer rats. This higher K ATP  channel expression is consistent with the BTB permeability results. The different expression of K ATP  channel in syngeneic and non-syngeneic rat models suggests difference in immunogenecity of 9L tumor cells in the two rat strains may have a role in regulating the expression of K ATP  channel while having less impact on K Ca  channel expression in tumors. Therefore, the relative expression of these two targets of biochemical modulation of BTB permeability in human glioma may help to develop strategies to enhance delivery of chemotherapeutic drugs to brain tumors.
Blocking Malaria Transmission
Authors: Joan Stephenson
Journal: JAMA (2004)

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Abstract 14713: SIRT6 Blocks Differentiation of Cardiac Fibroblasts into Myofibroblasts by Inactivation of the TGFβ1 Signaling
Authors: Nagalingam R Sundaresan, Madhu Gupta, Mahesh P Gupta
Journal: Circulation (2014)

Introduction: Cardiac fibrosis contributes to adverse cardiac remodeling which is precursor to heart failure. At the cellular level, fibrosis occurs because of differentiation of quiescent cardiac fibroblasts (CF) into myofibroblasts (myoFB), an activated fibroblast-like cell-type capable of synthesizing excessive extracellular matrix. Activation of TGFβ-signaling is considered to be a major contributor of this process. This study was undertaken to examine the role of SIRT6, an anti-aging molecule, on the differentiation of CF to myoFB and the development of cardiac fibrosis. Methods and Results: Cardiac fibroblasts obtained from human failing hearts were analyzed for expression levels of SIRT6 and myoFB markers like, smooth muscle α-actin (SMA), fibronectin and collagen1 (Col1) by western blotting. Expression levels of SMA, fibronectin and Col1 were increased, whereas SIRT6 levels were decreased in CF prepared from failing hearts, compared to control hearts. To test whether SIRT6 deficiency contributed to activation of myoFB markers, we analyzed hearts of SIRT6 (+/-) mice. There was robust activation of myoFB markers and Mason-trichome blue positive staining for fibrosis in SIRT6 (+/-) hearts, compared to controls. To understand the mechanism involved, we analyzed different components of TGFβ-Smad3 signaling in SIRT6 deficient hearts. Expression levels of both pro- and mature-TGFβ1 and Smad3 were significantly elevated in SIRT6 (+/-) hearts, compared to controls. By using siRNA approach we also knocked down SIRT6 (SIRT6-KD) levels in human control CF, and analyzed sensitivity of these fibroblasts to pro-fibrotic agonists, Ang-II. SIRT6-KD fibroblasts had significantly higher levels of TGFβ1, and they were highly sensitive to Ang-II stimulation in terms of synthesizing myoFB markers. Over expression of SIRT6 blocked the synthesis of TGFβ1 and the fibrotic response to Ang-II, both in control and in SIRT6-KD fibroblasts, thus demonstrating anti-fibrotic activity of SIRT6. Conclusions: These data indicate that SIRT6 is capable of blocking fibroblast differentiation into myofibroblasts by suppressing the synthesis of TGFβ1, and signify that SIRT6 could serve as a therapeutic target for the treatment of cardiac fibrosis and heart failure.
Effects of sleep disordered breathing, asthma and socio-economic status on behavioural parameters in children
Authors: Yasemin Gokdemir, Refika Ersu, Ayse Rodopman Arman, Pinar Ay, Ahmet Topuzoglu, Fatih Torlak, Bulent Karadag, Fazilet Karakoc
Journal: European Respiratory Journal (2011)

Background: Inner-city children with asthma have increased prevalence of sleep disordered breathing (SDB) and these children have more pronounced behavioral problems.

Aim: To study the effect of asthma and SDB on behavior in children by socio-economic status (SES).

Methods: This cross sectional study was performed in 6 primary schools; 3 with low and 3 with high SES. These schools were determined by a previous study which evaluated the SES of students. ISAAC questionnaire for asthma, pediatric sleep questionnaire for SDB and a standardized SES questionnaire were completed by the parents. Additionally, parents completed the Strengths and Difficulties Questionnaire (SDQ), a brief behavioral screening instrument which reflects emotional and peer problems (internalizing behaviors (IB)) besides conduct and hyperactivity problems (externalizing behaviors (EB)). The prosocial scores derived from SDQ indicated the psychosocial adjustment.

Results: 641 children (52% girls) were included to the study. Mean age was 8.7±1.0 years. Rates of ever wheezing, doctor-diagnosed asthma and SDB were 15.4%, 8.8% and 8.1%, respectively. The EB were higher in boys (p< 0.001) and problem behaviors tended to decrease by increasing SES (p< 0.05). Prosocial adjustment scores were higher in girls (p< 0.05). In the presence of ever wheezing and SDB; both IB and EB increased (p< 0.001 for both).

Conclusion: Increased rates of externalizing and internalizing problems in inner-city primary school children with SDB might reflect a negative impact on overall neurobehavioral health. Being male, coming from lower SES, and the presence of both wheezing and SDB might increase negative behavioral problems.