tbuckley/cabot-search huggingface dataset:
Pharmacokinetic profile of the base-excision repair inhibitor methoxyamine-HCl (TRC102; MX) given as an one-hour intravenous infusion with temozolomide (TMZ) in the first-in-human phase I clinical trial.
Authors: P. Sawides, Y. Xu, L. Liu, J. A. Bokar, P. Silverman, A. Dowlati, S. L. Gerson
Journal: Journal of Clinical Oncology (2010)

e13662 Background: MX, the first base excision repair (BER) inhibitor evaluated in humans, blocks the BER pathway by covalently binding to apurinic/pymidinic (AP) sites in DNA. Initial results of the administration of MX have been presented (AACR Annual Meeting 2009, abstract #5433). Pharmacokinetic (PK) analyses revealed a distinct PK profile different from that observed in mice and dogs, where half- life of MX was 19 minutes and 4.5 hours (h) respectively. In humans, MX half life is estimated to be 45.3 h (range: 32 − 68.8 h). As a result, the MX administration was adjusted from a 5-day intravenous (iv) continuous infusion (CI) to a 1-hour iv infusion. Methods: This ongoing phase I dose-escalation trial investigates the safety, PK, and pharmacodynamic (PD) profile of MX given as an one-hour iv infusion in combination with TMZ. PD markers, including analysis of AP sites measured on DNA extracted from patients' mononuclear cells (PBMCs) as well as DNA strand break determined by comet assay at multiple time points, are included. Results: 4 patients enrolled, at dose-level 1 (TMZ 100 mg/m2/day po, days 1-5 and MX 15 mg/m2 IV on day 1). Various primary tumors (lung, breast, pancreatic, skin adnexal) included. The average half-life of MX was 46.8 h (range: 20.4–62.7 h, based on 8 treatment cycles from 3 patients), not statistically different from the 5-day CI regimen. Treatment has been well tolerated. One grade 3 toxicity possibly treatment related (hallucinations in one patient with progressive disease and on opioids). PD results showed that administration of the combination of TMZ and MX resulted in 30–60% reduction in detectable AP sites. Comet assay results revealed that the combination of TMZ and MX induced a 2 to 3-fold higher levels of DNA strand breaks compared to TMZ alone. Conclusions: Initial data demonstrate that MX in combination with TMZ is well tolerated. MX has a distinct PK profile in humans, which has allowed us to move to a convenient one-hour infusion regimen. PD demonstration of MX's biologic activity on patients' mononuclear cells has been demonstrated even at the first dose level. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration TRACON TRACON
Metabolic Effects of Alcohol on the Liver
Authors: Kurt J. Isselbacher, Norton J. Greenberger
Journal: New England Journal of Medicine (1964)

Fatty Liver Associated with Alcohol AdministrationIt has been observed in laboratory animals9, 49 50 51 that an acute fatty liver can follow the administration of alcohol, usually after moderate or excessive doses. It is quite likely that a similar phenomenon occurs in man.52 A number of investigators have recently made considerable efforts to elucidate the mechanisms whereby this lipid accumulation may occur. Five possible mechanisms or factors, depicted in Figure 5, alone or in combination might be involved: increased mobilization of fatty acids from peripheral adipose-tissue depots; increased hepatic fatty acid synthesis; decreased utilization or oxidation of fatty acids by the liver; increased . . .
Abstract P428: Get Active Orlando: Walking, Bicycling, Gardening
Authors: Jonathan W Decker, Karen E Dennis
Journal: Circulation (2013)

Introduction Research has consistently demonstrated positive benefits from physical activity (PA) in the primary and secondary prevention of chronic diseases and conditions such as CVD. Even the person going from doing nothing to doing something will see the benefits. The specific aim of this study was to implement and evaluate the short-term effects of walking, bicycling, and community gardening approaches to enhancing PA among urban-dwelling older adults and low-income ethnic minorities. Methods Participants included 157 adults of all races/ethnicities who self-selected into one of three interventions: walking ( n = 47), bicycling ( n = 35), or gardening ( n = 75). Interventions were 10 weeks long, with follow-up data collection every 3 months until 1 year. Data collection included self-report questionnaires (Self-efficacy for Exercise Habits Survey, Lubben Social Network Scale, Perceived Environments Attributes scale, Behavioral Risk Factor Surveillance System, self-reported frequency, duration, and distance of PA performed), measured PA (7-day accelerometry), and PA focus groups. Results Throughout the course of the intervention and the 9-month follow-up period, only three significant differences in self-reported questionnaire data arose. These differences occurred among bicyclists, with a significant increase ( p &lt; 0.01) in social networks from pre- to post-intervention, which remained stable across time, to the 9-month data collection. The bicyclists also reported a significant improvement ( p &lt; 0.001) in the perceived environmental attributes. Bicyclists also reported an increase in duration, frequency, and distance of bicycling. Themes emerging from the focus groups included: meeting new people, a spirit of community, accountability, increasing exercise, and developing community awareness. Conclusions The purpose of this study was to increase the overall PA of the participants, not specific exercise routines. However, there were no significant differences from pre- to post-intervention (3 month interval) or to the 9-month follow-up except for the increase in social networks and perceived environmental attributes reported by the bicyclists. They also reported an increase in duration, frequency and distance ridden. In this study, gardening was the most successful intervention, with a greater percentage of individuals who wanted to participate, completed data collection, and continued beyond that time. Walkers demonstrated a lack of sustainability past the intervention period among individual participants. Although there were few statistically significant findings regarding PA and its influences, the results should be considered in their entirety. Participant verbal comments and feedback throughout the study, in addition to during focus groups, reflected the positive impacts that these interventions had upon the participants’ lives.
Impact of Sex on Morbidity and Mortality Rates After Lower Extremity Interventions for Peripheral Arterial Disease
Authors: Elizabeth A. Jackson, Khan Munir, Theodore Schreiber, Jeffrey R. Rubin, Robert Cuff, Katherine A. Gallagher, Peter K. Henke, Hitinder S. Gurm, P. Michael Grossman
Journal: Journal of the American College of Cardiology (2014)
Abstract 17773: Patients with Low Plasma High Density Lipoprotein-Cholesterol due to Mutations in the Gene Encoding for Lecithin: Cholesterol Acyl Transferase have Increased Atherosclerosis: A 3.0 Tesla MRI Study.
Authors: Adriaan G Holleboom, Rafael Duivenvoorden, Bas van den Bogaard, Eric de Groot, Aart J Nederveen, J. S Lameris, Barbara A Hutten, John J Kastelein, Jan A Kuivenhoven, Erik S Stroes
Journal: Circulation (2010)

Background: The role of low plasma levels of high density lipoprotein-cholesterol (HDL-c) as a causal factor in atherogenesis has been questioned recently, particularly in view of the absent relati...
Abstract 314: Risk of Aspiration and Early-Onset Pneumonia After Emergency Ventilation: A Comparison of Laryngeal Tube and Endotracheal Intubation
Authors: Joerg Honold, Jan Hodrius, Thomas Schwietz, Andreas Zeiher, Florian Seeger
Journal: Circulation (2014)

Introduction: Laryngeal tubes (LT) have substantially facilitated emergency airway management. Currently, the LT shows increasing use. However, it remains unclear whether LT provides comparable protection against aspiration or not even higher rates of aspiration and pneumonia, compared to endotracheal intubation (ET) as former gold standard.

Hypothesis: LT are not associated with higher rates of pulmonary aspiration

Methods: Retrospective analysis for aspiration and early-onset pneumonia in patients (pts) after preclinical airway management by either LT or ET. Further, in-hospital mortality was analyzed.

Results: 90 pts with ventilation by either ET (n= 69) or LT (n=21) were included in the study. Pts were not included if indication for ventilation was pneumonia, aspiration, drowning or if they had preexisting tracheotomy. ET and LT-group did not differ regarding age (ET: 62±16 yrs, LT: 64±8 yrs, p=0.56), female gender (ET: 23.2%, LT: 33.3%, p=0.25), or first paO2/FiO2 (ET: 300±164, LT: 342±178, p=0.3). The majority of pts were survivors of out-of-hospital cardiac arrest (OHCA, 72.2%), with a significant higher OHCA-rate in the LT-group (LT: 95.2% ET: 65.2%, p = 0.006).

Analysis for pulmonary aspiration revealed a higher aspiration rate in the ET-group (43.5%, LT: 23.8%, p = 0.08), especially after OHCA (ET: 48.9%, LT: 20%, p=0.025).

In parallel, early-onset pneumonia as correlate for microaspiration was observed more frequent in ET-pts (41% vs. 25%, p= 0.21). In OHCA-patients without aspiration, rates of pneumonia were similar (ET: 26.1%, LT: 25%; p=0.62).

Analysis of in-hospital mortality showed a significant higher mortality in the LT-group (57.1% vs 30.4%, p=0.026). Also in OHCA-pts, higher mortality was observed in the LT-group (60% vs. 28.9%, p=0.018). By multivariate analysis for in-hospital mortality, only a low first pH was identified as independent predictor of death (HR 0.064, 95% CI 0.006-0.635, p=0.019).

Conclusions: Airway management by LT was not associated with higher risk of aspiration. In contrast, higher rates of aspiration and pneumonia were observed after ET, especially in OHCA-pts. However, a prognostic impact of LT remains to be elucidated.
Abstract 15403: Dishevelled-Induced Cardiomyopathy is Rescued by Deletion of Calcium/Calmodulin-Dependent Protein Kinase II
Authors: Min Zhang, Pratima Malekar, Marco Hagenmueller, Marco Ochs, Johannes Backs, Hugo A Katus, Stefan E Hardt
Journal: Circulation (2011)

Background: Our previous findings have shown that cardiac overexpression of Dishevelled 1 (Dvl-1) results in cardiomyopathy. Recently, growing lines of evidence document Calcium/calmodulin-dependen...
Rehabilitation for chronic low back pain
Authors: C. Price, A. C d. C Williams, C. J Main, J. Guzman, R. Esmail, K. Karjalainen, A. Malmivaara, C. Bombardier
Journal: BMJ (2001)

Editor—We have misgivings about the conclusions drawn by Guzman et al on multidisciplinary rehabilitation for chronic low back pain.1 Low back pain problems are as heterogeneous as the wider category of chronic pain, and in disregarding systematic reviews and meta-analyses of multidisciplinary rehabilitation in chronic pain Guzman et al have missed a large body of relevant evidence, including trials of cost effectiveness.2,3

Standard quality criteria used for randomised controlled trials cannot be applied in an unmodified form to psychological treatments, which constitute important components of multidisciplinary rehabilitation. The impossibility of blinding patients and therapists need not lower standards. Several trials reviewed employed recognised methods for establishing treatment equivalence: patient rating of treatment credibility or expectations; manualised treatments; blind rating by experts of treatment excerpts; and close supervision of therapists. It is disappointing to see the Cochrane Back Review Group continuing to apply inappropriate criteria and thereby misjudging methodological quality of trials.

Variability in outcome arises from heterogeneity among patients, differences in treatment, and their interaction, not only from length of treatment. Content of treatment is far more important than the total time of the programme. Physical treatment alone, as Guzman et al say, is a weak way to change behaviour, particularly in relation to work and use of health care. Patients who have become fearful of further pain and damage, and who are disabled as much by their fears and misapprehensions as by the pain itself,4 need psychologically based treatment, which is still in short supply.

The emphasis on return to work as the primary outcome is inappropriate when the population includes homemakers, as did several of the trials reviewed. Disability or function is a broader issue and includes the important, but neglected issue, of change in use of healthcare resources. An undue focus on return to work to define effectiveness leads to restricting access to treatment for non-workers, particularly among older patients.

Guzman et al acknowledge that their conclusions may not apply in primary care, but patients are better defined by their level of disability than by the setting in which they are seen, and their treatment defined not by hours but by its adequacy to restore as near as possible normal function, whether in secondary prevention of recently injured workers or chronically disabled non-workers.5 This review offers clinicians little help in selecting the right level of treatment for patients with low back pain.
Psychological Treatments for Orphans and Vulnerable Children Affected by Traumatic Events and Chronic Adversity in Sub-Saharan Africa
Authors: Peter Ventevogel, Paul Spiegel
Journal: JAMA (2015)

This From The JAMA Network describes a recently published study in JAMA Pediatrics that assessed trauma-focused cognitive behavioral therapy for orphans and vulnerable children with trauma-related symptoms in Zambia.
Flow Cytometric Detection of BCR-ABL Fusion Proteins in Leukemia Patients Via An Immunobead Assay
Authors: Floor Weerkamp, E. Dekking, Vincent H.J. Van der Velden, Sebastian Böttcher, Nancy Boeckx, Elisabeth R. Van Wering, Juan Flores Montero, Paulo Lucio, Lukasz Sedek, Tomas Kalina, Elizabeth Macintyre, Frank J.T. Staal, Jacques JM van Dongen
Journal: Blood (2008)
Abstract 5301: Flecainide Blocks Cardiac Ryanodine Channels and Prevents Catecholaminergic Ventricular Tachycardia in Cardiac Calsequestrin Null Mice
Authors: Nagesh Chopra, Hiroshi Watanabe, Derek Laver, Hyun S Hwang, Dan M Roden, Bjorn C Knollmann
Journal: Circulation (2008)
Abstract 2956: Twenty Year Prognosis of Coronary Artery Bypass Grafting for Coronary Stenosis caused by Kawasaki Disease
Authors: Etsuko Tsuda, Soichiro Kitamura, Junjiro Kobayashi, Ken Watanabe, Hideo Ohuchi, Shigeyuki Echigo, Toshikatsu Yagihara
Journal: Circulation (2007)
Scientific misconduct in Croatia
Authors: Matko Marusic
Journal: BMJ (2008)

In the wake of the reaction of academic institutions in Croatia to Chalmers’s account of repeated plagiarism by Croatian clinician Asim Kurjak,1 the BMJ called on Zagreb University School of Medicine to take action,2 whose court of honour had recently failed to act on proved allegations of Kurjak’s misconduct. After a request that both the BMJ and the Croatian Medical Journal investigate the articles …
A fibril-based structural constitutive theory reveals the dominant role of network characteristics on the mechanical behavior of fibroblast-compacted collagen gels
Authors: Zhonggang Feng, Yuki Ishiguro, Kyohei Fujita, Tadashi Kosawada, Takao Nakamura, Daisuke Sato, Tatsuo Kitajima, Mitsuo Umezu
Journal: Biomaterials (2015)
Treatment Outcome and Prognostic Factors of Korean Patients with Chronic Lymphocytic Leukemia: Multicenter Retrospective Study
Authors: Yunsuk Choi, Jung-Hee Lee, Chul Won Jung, Jin Seok Kim, Inho Kim, Silvia Park, June-Won Cheong, Seonyang Park, Sung-Yong Kim, Mark Hong Lee
Journal: Blood (2014)
Abstract 17067: Circulating Lipoprotein (a) Level, Apolipoprotein (a) Isoform Size, and Risk of Unexplained Ischemic Stroke in Younger Adults (The THrombophilia in Cryptogenic stroKe [THICK] Study)
Authors: Azadeh Beheshtian, Sanyog Shitole, Alan Z Segal, Russell P Tracy, Daniel Rader, Richard B Devereux, Jorge R Kizer
Journal: Circulation (2014)

Background:  Lipoprotein (a) [Lp(a)] comprises an apolipoprotein (a) [apo(a)] molecule that contains a variable number of kringle IV type 2 (KIV-2) repeats. KIV-2 number determines Lp(a) size but relates inversely to serum Lp(a) levels. Both smaller apo(a) isoforms and higher Lp(a) levels have been linked to coronary heart disease and, less so, stroke, but their independent contributions are less well defined. The role of Lp(a) in younger adults with cryptogenic stroke remains largely unexamined.   Methods:  We evaluated Lp(a) and apo(a) isoforms in a prospective case-control study of prothrombotic risk factors for unexplained ischemic stroke in subjects ages 18 to 64. Cases consisted of patients admitted to Weill Cornell Medical Center (2002 [[Unable to Display Character: –]] 2011) with cryptogenic stroke based on modified TOAST criteria. Controls included volunteers recruited from the area. Lp(a) was measured in 255 cases (≥2 months post stroke) or 390 controls with both a molecular-weight (KIV-2 number) independent and a molecular-weight dependent immunoturbidimetric assay. Apo(a) isoform size was determined by agarose gel electrophoresis.   Results:  Cases and controls were similar for most characteristics (median age 46 vs 44; women, 39 vs 46%; white 60 vs 63%, black 13 vs 12%, Hispanic 17 vs 18%), but cases had more frequent hypertension, diabetes, smoking, and migraine with aura. In race-specific analyses, Lp(a) levels showed positive associations with cryptogenic stroke in whites, but not in the smaller subgroups of blacks and Hispanics. After full adjustment, comparison of the highest to the lowest quartile in whites was significant for molecular-weight-independent (OR=2.10 [95% CI=1.03, 4.27]), and near-significant for molecular-weight-dependent Lp(a) (OR=1.86 [95% CI=0.97, 3.55]). These associations were unchanged with significant adjustment for apo(a) size. By contrast, apo(a) size was not significantly associated with cryptogenic stroke in any ethnic subgroup.   Conclusions:  This study shows that Lp(a) level, but not apo(a) isoform size, is an independent risk factor for unexplained ischemic stroke in young and middle-aged adults of European descent. Future studies will need to examine this association in sufficiently powered samples for other ethnic groups.
Abstract 16140: Primary Payer Status Affects Mortality for Coronary Artery Bypass Grafting Operations
Authors: Damien J LaPar, Castigliano M Bhamidipati, Matthew L Stone, Richard A Guyer, Christine L Lau, Irving L Kron, Gorav Ailawadi
Journal: Circulation (2011)

Objectives: Medicaid and Uninsured populations are a significant focus of current healthcare reform. We hypothesized that outcomes following coronary artery bypass grafting (CABG) in the United Sta...
Abstract 16237: Striking Electrophysiologic Differences Between Cardiac Sodium Channel Isoforms SCN10A and SCN5A
Authors: Tao Yang, Thomas C Atack, Robert L Abraham, Dawood Darbar, Dan M Roden
Journal: Circulation (2011)

Introduction: Single nucleotide polymorphisms (SNPs) in the SCN10A locus have been implicated by genome-wide association as modulators of PR and QRS durations. SCN10A encodes the TTX-resistant sodi...
Authors gave distorted view through selective citation
Authors: D. Ross, M. Whitehead, J. Stevenson
Journal: BMJ (1996)

EDITOR,—What women most certainly do not need is Elizabeth H Price and Helen Kaye Little's highly selective citation of the literature.1 The authors refer to an editorial by McPherson, which stated that five years' use of hormone replacement therapy is associated with a 50% increase in the risk of breast cancer.2 They express surprise that research in which McPherson participated should have found that 55% of postmenopausal female doctors choose nevertheless to take hormone replacement therapy.3 They explain this figure as …
Abstract 4375: Length of Stay and Reasons for Prolonged Length of Stay After Transcatheter Aortic Valve Implantation
Authors: Rutger-Jan Nuis
Journal: Circulation (2009)

Aims - Although transcatheter aortic valve implantation (TAVI) has been associated with encouraging short term outcomes, there is a paucity of data regarding in-hospital length of stay (LOS) and re...
Incidental LV LGE on CMR Imaging in Atrial Fibrillation Predicts Recurrence After Ablation Therapy
Authors: Promporn Suksaranjit, Nazem Akoum, Eugene G. Kholmovski, Gregory J. Stoddard, Lowell Chang, Kavitha Damal, Krishna Velagapudi, Allen Rassa, Erik Bieging, Shridhar Challa, Imran Haider, Nassir F. Marrouche, Christopher J. McGann, Brent D. Wilson
Journal: JACC. Cardiovascular imaging (2015)
Abstract 17049: Upregulation of the Matricellular Protein Thrombospondin (TSP)-1 in the db/db Heart Regulates Matrix Remodeling and Induces Vascular Rarefaction
Authors: Carlos Gonzalez-Quesada, Anna Biernacka, Dong-Wook Lee, Na Li, Marcin Dobaczewski, Nikolaos G Frangogiannis
Journal: Circulation (2011)

The matricellular protein Thrombospondin (TSP)-1, a potent angiostatic agent and crucial TGF-β activator, is markedly upregulated in animal models of obesity and diabetes and in tissues from diabetic patients; however, its role in the pathogenesis of diabetic complications is unknown. Leptin resistant db/db mice rapidly develop obesity and diabetes and exhibit cardiac hypertrophy, fibrosis and diastolic dysfunction as they age. We hypothesized that TSP-1 induction in the db/db heart may regulate cardiac remodeling and fibrosis. TSP-1 expression was markedly upregulated in db/db hearts. In order to dissect the role of TSP-1 in diabetic cardiomyopathy we generated db/db TSP-1 -/- (dbTSP-1) mice and we studied the effects of TSP-1 absence on the metabolic and cardiac dysfunction associated with central leptin resistance. TSP-1 absence did not affect weight gain and fat content in db/db mice. Mortality was comparable between db/db and dbTSP-1 mice. dbTSP-1 mice had significant alterations in chamber geometry exhibiting increased left ventricular dilation (LVEDV, db/db:73.36+2.03 vs. dbTSP1:90.14+5.85 p&lt;0.01) associated with a modest deterioration in systolic function (FS, db/db: 41.82+1.07 vs. dbTSP1:31.02+1.59 p&lt;0.01). In order to dissect the mechanisms responsible for chamber dilation in dbTSP-1 mice, we examined the effects of TSP-1 absence on matrix remodeling. Using a hydroxyproline assay, we found that TSP-1 loss reduced collagen deposition in db/db animals. Decreased cardiac fibrosis in dbTSP-1 mice was associated with diminished TGF-β/Smad3 signaling and attenuated MMP activity in the myocardium. Moreover, db/db hearts exhibited an aging-associated vascular rarefaction in the myocardium that was attenuated in dbTSP-1 animals (capillary density, WT: 4311.6+313.17 vs. db/db: 2994+133 vs. dbTSP1 3659.1+60.9 p&lt;0.01). Our findings demonstrate that, while inducing TGF-β activation and cardiac fibrosis, TSP-1 induction in obese diabetic hearts plays a role in maintaining matrix homeostasis, thus protecting the myocardium from dilative remodeling. Moreover, TSP-1 upregulation is, at least in part, responsible for reduced angiogenesis in the hypertrophied diabetic heart, leading to formation of a rarefied capillary network.