tbuckley/cabot-search huggingface dataset:
Late-breaking abstract: Sildenafil for chronic obstructive pulmonary disease: A randomized crossover trial
Authors: David Lederer, Matthew Bartels, Neil Schluger, Frances Brogan, Patricia Jellen, Byron Thomashow, Steven Kawut
Journal: European Respiratory Journal (2011)

Background: Pulmonary hypertension with exercise is common in chronic obstructive pulmonary disease (COPD) and may contribute to exercise limitation in this disease. We aimed to determine the effects of treatment with sildenafil on exercise capacity in patients with COPD and emphysema.

Methods: We performed a randomized, double-blind, placebo-controlled two-period crossover trial of sildenafil thrice daily in ten adults with COPD and emphysema on CT scan. We randomized study participants to four weeks of sildenafil (or placebo) followed by a one-week washout and then four weeks of placebo (or sildenafil). The two primary outcomes were the six-minute walk distance and oxygen consumption at peak exercise.

Results: The study subjects had a mean age of 66 years, and 80% were male. The mean ± standard deviation FEV1 was 38±17% predicted. Sildenafil had no effect on six minute walk distance (placebo-corrected difference = -7.8 m, 95% confidence interval, -23.2 to 7.5 m, p = 0.35) or oxygen consumption at peak exercise (placebo-corrected difference = -0.1 ml/kg/min, 95% confidence interval -2.1 to 1.8 ml/kg/min, p=0.89). Sildenafil increased the alveolar-arterial oxygen gradient (p=0.02), worsened symptoms (p=0.04), and decreased quality-of-life (p=0.03). Adverse events were more frequent while receiving sildenafil (p=0.005).

Conclusions: Routine sildenafil administration did not have a beneficial effect on exercise capacity in patients with COPD and emphysema. Sildenafil significantly worsened gas exchange at rest and quality of life.
PET study of competition between intravenous cocaine and [11C]raclopride at dopamine receptors in human subjects
Authors: T E Schlaepfer, G D Pearlson, D F Wong, S Marenco, R F Dannals
Journal: American Journal of Psychiatry (1997)

Animal data suggest that the strong euphoriant effects of cocaine are related to the drug's enhancement of available dopamine at the synaptic cleft. The authors' goal was to determine whether this mechanism is the same in humans because the development of putative pharmacological agents for treatment of cocaine dependence depends on this knowledge.Positron emission tomography with [11C]raclopride was used to examine the effects of the intravenous administration of 48 mg of cocaine (a typical "street" dose) on the occupancy of dopamine 2 receptors in the putamen of 11 self-identified intravenous drug abusers.All 11 subjects reported subjective stimulation and euphoria in response to cocaine administration. Radioligand occupancy at dopamine receptors was decreased significantly after cocaine administration, suggesting that higher dopamine concentrations were competing at the receptor site.These results support the concept of dopamine system involvement in human cocaine abuse.
Ethical debate: Results of genetic testing: when confidentiality conflicts with a duty to warn relatives Case study Act to resolve conflict View from Dutch general practice Family duty is more important than rights
Authors: W.-C. Leung, E C M Mariman, J. C van der Wouden, H. van Amerongen, C. Weijer
Journal: BMJ (2000)

# Results of genetic testing: when confidentiality conflicts with a duty to warn relatives {#article-title-2} When a patient is found to have an inherited disease it has implications for the whole family. If screening is available the test is usually offered to all relatives who could be affected, but what if the patient does not want to tell his family about his diagnosis? # Case study {#article-title-3} As his general practitioner, you referred Andrew, a 23 year old man, to the local psychiatrist with gradual onset of paranoid ideation. From the hospital correspondence, you gather the psychiatrist detected dysarthria and abnormal involuntary movements and asked for a neurologist's opinion. The neurologist diagnosed Wilson's disease (hepatolenticular degeneration) and Andrew was started on chelation therapy in a specialist centre. You know Andrew's background reasonably well as you also act as the general practitioner for his 21 year old brother, Martin, and his 20 year old sister, Alison. Their father died many years ago in a road traffic accident and their mother died of breast cancer two years ago. Andrew lived with Martin and Alison until last year, when he moved out to live with his girlfriend, partly due to his increasing mistrust of Martin and Alison. As Wilson's disease is autosomal recessive in inheritance, both Martin and Alison have a 1 in 4 risk of having the disease. The disease is treatable in the presymptomatic stage, and you are anxious to ensure that Martin and Alison receive appropriate counselling and testing. However, you learn from Andrew that Martin and Alison have not received such counselling. Indeed, when the staff at the specialist centre asked Andrew whether he had any siblings, he replied that he had none. Although you carefully explained to Andrew the importance of Martin and Alison receiving early counselling and testing, Andrew is clear that he does not want anyone to inform them about his recent diagnosis. He seems … Correspondence to: J C van der Wouden.
Abstract 9487: Implantation of Scaffold-Free Tubular Tissue Using a Bio-3D Printer Augments Vascular Remodeling and Endothelialization
Authors: Manabu Itoh, Koichi Nakayama, Ryo Noguchi, Keiji Kamohara, Kojirou Furukawa, Kazuyoshi Uchihashi, Shuji Toda, Jun-ichi Oyama, Koichi Node, Shigeki Morita
Journal: Circulation (2014)

Introduction: Small caliber synthetic vascular grafts are not clinically available. We developed a novel method to create scaffold-free tubular tissue from multicellular spheroids (MCS) using a “Bio-3D printer”-based system, which enables the creation of various three-dimensional structures pre-designed using a computer system. With this system, we created a tubular structure (Fig. 1), and studied its biological features. Methods: We made 1.5 mm in diameter scaffold-free tubular tissues from MCS (1.25 x 10[[Unable to Display Character: &amp;#8311;]] cells) composed of human umbilical vein endothelial cells (40%), human aortic smooth muscle cells (10%) and normal human dermal fibroblasts (50%) using a Bio-3D printer. The vessels were cultured in a perfusion system. We implanted grafts into the abdominal aortas of F344 nude rats, and assessed the flow by ultrasonography and performed histological examinations on the second (N=5) and fifth (N=5) days after implantation. Results: All grafts were patent. Remodeling of the vessel (enlargement of the lumen area and thinning of the wall) was observed (Fig. 2). A layer of endothelial cells was developed after implantation of the graft (Fig. 3). Conclusions: The scaffold-free vascular grafts made of MCS using a Bio-3D printer showed biological features comparable to native vessels. Further studies are warranted toward the clinical application of this novel technology.
Understanding the Cellular and Molecular Mechanisms of Physical Activity-Induced Health Benefits
Authors: P. Darrell Neufer, Marcas M. Bamman, Deborah M. Muoio, Claude Bouchard, Dan M. Cooper, Bret H. Goodpaster, Frank W. Booth, Wendy M. Kohrt, Robert E. Gerszten, Mark P. Mattson, Russell T. Hepple, William E. Kraus, Michael B. Reid, Sue C. Bodine, John M. Jakicic, Jerome L. Fleg, John P. Williams, Lyndon Joseph, Mary Evans, Padma Maruvada, Mary Rodgers, Mary Roary, Amanda T. Boyce, Jonelle K. Drugan, James I. Koenig, Richard H. Ingraham, Danuta Krotoski, Mary Garcia-Cazarin, Joan A. McGowan, Maren R. Laughlin
Journal: Cell Metabolism (2015)
Adjustment of DOSE of ifosfamide (If.) in children after the first treatment session
Authors: B. Gourmel III, L. Ginefri, S. Alkallaf, N. Delépine
Journal: Journal of Clinical Oncology (2008)

10038 Background: Ifosfamide (If) is one of the current reference agents for the treatment of sarcoma in children. Treatment comprises several courses (4 or 5) of If. administered as a continuous infusion. 60 patients,18 over 4 treatment sessions, aged from 6 to 21 years and suffering from bone and soft tissue sarcoma were followed during their treatment session (5 days, 3g/m2/d). This prodrug, capable of autoinduction, is metabolized to produce the dechloroethylated metabolites 2DIf and 3DIf, responsible of the neurotoxicity, or with hydroxylation to produce 4 OH If the alkylating compound. The goal of this study was to determine if neurotoxicity and alkylating potential can be estimated after the first treatment session. Methods: Blood samples were withdrawn each day of the infusion (T 0,24,48,72,96 and 120h). Determination of each compound (If, 2DIf and 3DIf. and 4OHIf.) were performed using GC/NPSD method. PK analysis was performed on the basis of Area under Curve (AUC) for Ifos. and metabolites using Excel Spreadsheet. Results: We calculated the metabolite index (MI) : ratio of the cumulated AUC metabolite / AUC If, for each day. The global pharmacokinetic profiles for the different treatment sessions showed a similar shape. Ifos blood levels raised to a maximum at the end of day1, then they regularly decreased. The percentage of induction was equal to 48.9% ±21.2%. The MI.of 2DIf. and 3D If showed a continuous increase mainly important during the 3 first days and then reach a relative steady state. The final values were respectively 18.5%± 8.7% and 22.9%± 5.3%. The MI of 4OHIf confirmed the previous increase of its amount. The final value for this compound was 2.3%±0.8%. For a given patient, no significant differences were demonstrated for the variation of MI during the infusion whatever treatment session (1 to 4) was considered. Consequently, at the end of the first infusion, calculation of the MI inform us on the comportment of the patient toward the drug. Conclusions: The difference between the MI average reported above and the patient MI is applied to reduce or increase the next course. Potential risk of neurotoxicity is minimized by a reduced dose. Low MI of the 4OHIf metabolite is followed by an increased dose. This method in now applied routinely and no major toxicity have been noted. No significant financial relationships to disclose.
Nucleotide excision repair genes and lung cancer risk: A pathway-based approach
Authors: Jian Gu, Yunfei Wang, Jie Lin, Maosheng Huang, Qiong Dong, Margaret R. Spitz, Xifeng Wu
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2560 

Nucleotide excision repair (NER) is one of the major DNA repair pathways in mammalian cells, involved in the removal of a wide variety of DNA lesions including bulky carcinogen adducts from tobacco exposure. Polymorphisms in NER genes may influence DNA repair capacity and confer cancer susceptibility. To explore the association between these polymorphisms and lung cancer risk, we examined ten polymorphisms in six major NER genes in 1396 lung cancer patients and 1423 age-, gender- and smoking-matched controls. The specific polymorphic loci examined include: XPA (A/G at 5’ UTR), XPC (polyAT, Ala499Val, Lys939Gln), XPD (Asp312Asn, Lys751Gln), XPF (Ser662Pro), XPG (His1104Asp), ERCC6 (Met1097Val, Arg1230Pro). For main effects of the individual polymorphisms, only the variant XPA alleles had a significant impact on lung cancer risk (OR=0.80, 95%: 0.64-0.99). There were no statistically significant differences in the distributions of the other polymorphisms between the cases and the controls. However, there was a significant trend for an increased risk of lung cancer with an increasing number of putative high-risk alleles. Using individuals with less than 3 putative high-risk alleles as the reference group, individuals with 3, 4 and more than 4 risk alleles had adjusted ORs of 1.14 (0.87-1.49), 1.40 (1.08-1.81) and 1.68 (1.32-2.12), respectively, ( P for trend < 0.000). When we dichotoimized the subjects at ≥4 or <4 putative risk alleles, individuals with ≥4 risk alleles had a significantly elevated lung cancer risk (OR=1.46, 95%: 1.24-1.73) as compared to those with <4 risk alleles. The risk was more evident in men (OR=1.72, 95%: 1.35-2.18) compared to women (OR=1.25, 95%: 0.98-1.58); in younger individuals (OR=1.63, 95%: 1.27-2.09) compared to older individuals (OR=1.31, 95%: 1.04-1.65); in ever smokers (OR=1.52, 95%: 1.27-1.81) compared to never smokers (OR=1.11, 95%: 0.74-1.81); and in heavy smokers (OR=1.88, 95%: 1.48-2.39) compared to light smokers (OR=1.14, 95%: 0.90-1.45). This large study offers a pathway-based analysis of multiple polymorphic genes and the data suggest that individuals with higher number of genetic variations in DNA repair genes in a common pathway are at increased risk for lung cancer, confirming the importance of taking a pathway-based approach to risk assessment. Supported by NCI grants CA 55769, CA 70907 and CA 86390 .
Association of Reduced Type IX Collagen Gene Expression in Human Osteoarthritic Chondrocytes With Epigenetic Silencing by DNA Hypermethylation
Authors: Kei Imagawa, María C. de Andrés, Ko Hashimoto, Eiji Itoi, Miguel Otero, Helmtrud I. Roach, Mary B. Goldring, Richard O. C. Oreffo
Journal: Arthritis & Rheumatology (2014)

Objective To investigate whether the changes in collagen gene expression in osteoarthritic (OA) human chondrocytes are associated with changes in the DNA methylation status in the COL2A1 enhancer and COL9A1 promoter. Methods Expression levels were determined using quantitative reverse transcription–polymerase chain reaction, and the percentage of DNA methylation was quantified by pyrosequencing. The effect of CpG methylation on COL9A1 promoter activity was determined using a CpG‐free vector; cotransfections with expression vectors encoding SOX9, hypoxia‐inducible factor 1α (HIF‐1α), and HIF‐2α were carried out to analyze COL9A1 promoter activities in response to changes in the methylation status. Chromatin immunoprecipitation assays were carried out to validate SOX9 binding to the COL9A1 promoter and the influence of DNA methylation. Results Although COL2A1 messenger RNA (mRNA) levels in OA chondrocytes were 19‐fold higher than those in the controls, all of the CpG sites in the COL2A1 enhancer were totally demethylated in both samples. The levels of COL9A1 mRNA in OA chondrocytes were 6,000‐fold lower than those in controls; 6 CpG sites of the COL9A1 promoter were significantly hypermethylated in OA patients as compared with controls. Treatment with 5‐azadeoxycitidine enhanced COL9A1 gene expression and prevented culture‐induced hypermethylation. In vitro methylation decreased COL9A1 promoter activity. Mutations in the 5 CpG sites proximal to the transcription start site decreased COL9A1 promoter activity. Cotransfection with SOX9 enhanced COL9A1 promoter activity; CpG methylation attenuated SOX9 binding to the COL9A1 promoter. Conclusion This first demonstration that hypermethylation is associated with down‐regulation of COL9A1 expression in OA cartilage highlights the pivotal role of epigenetics in OA, involving not only hypomethylation, but also hypermethylation, with important therapeutic implications for OA treatment.
Abstract 19807: Pre-Superior Cavopulmonary Anastomosis Cardiac Catheterization at Altitude
Authors: Michael V Di Maria, Thomas E Fagan, Neil Wilson, Max B Mitchell, David N Campbell, James Jaggers, Eduardo da Cruz, D. Dunbar Ivy, Adel K Younoszai
Journal: Circulation (2014)

Introduction: Infants with single ventricle physiology typically undergo cardiac catheterization prior to superior cavopulmonary anastomosis (SCPA) to assess operative suitability. Predictors of poor outcome at sea level include elevated central venous pressure (CVP), transpulmonary gradient (TPG), pulmonary vascular resistance (PVR) and pulmonary artery (PA) size. Living at higher altitude has vasoconstrictive effects on the pulmonary vasculature, and a prior study suggested that higher PA pressure may predict worse outcomes. The goal of this study was to determine which elements of the pre-SCPA catheterization were useful in predicting successful Fontan operation at altitude. Methods: A retrospective review revealed 150 patients who underwent pre-SCPA catheterization over a 10-year period. Pre-SCPA catheterization data were abstracted and subjects were grouped by progression to Fontan vs. aborted palliation, heart transplant or death. Statistical analysis included Wilcoxon Rank Sum tests, uni-variable logistic regression and receiver operator characteristic (ROC) curve analysis. Results: Differences between groups at cardiac catheterization are summarized in Table 1. Logistic regression showed that larger PA diameter was protective; left PA: OR: 0.73, 95% CI: 0.6-0.9, p = 0.01; right PA: OR:0.73, 95% CI: 0.6-0.9, p = 0.02. ROC analysis defined thresholds for minimum left PA and right PA diameter of &lt;4mm for poor outcome (area under the curve of 0.68 and 0.67, respectively). Conclusions: Our data suggest that pulmonary arterial size, more so than measured pressure or resistance, influences ability to achieve Fontan palliation at higher altitude. We hypothesize that this may be a feature of differences in pulmonary arterial growth. An alternative approach to evaluating pulmonary arterial morphology during palliation, such as cross-sectional imaging, may help optimize individual patient hemodynamics and provide better predictors of outcome.
Improved outcome with hematopoietic stem cell transplantation in a poor prognostic subgroup of patients with mixed-lineage-leukemia-rearranged acute leukemia: Results from a prospective, multi-center study
Authors: Wang Yu, Liu Qi‐Fa, Qin Ya‐Zhen, Liu Dai‐Hong, Xu Lan‐Ping, Jiang Bin, Jiang Qian, Dai Min, Yu Si‐Jian, Jiang Xin‐Miao, Liu Yan‐Rong, Huang Xiao‐Jun
Journal: American Journal of Hematology (2013)

The purpose of this study is to define the role for allogeneic hematopoietic stem cell transplantation (allo‐HSCT) in mixed‐lineage‐leukemia (MLL)‐rearranged acute leukemia, which is now poorly understood. A prospective, multi‐center cohort study to determine whether allo‐HSCT could decrease relapse rates and improve long‐term survival of MLL+ leukemia patients was performed. Fifty‐six consecutive patients diagnosed with MLL–rearranged acute leukemia undergoing allo‐HSCT from two transplant centers in China were enrolled between October 2007 and October 2012. The trial was registered at www.chictr.org as # ChiCTR‐ONC‐12002739. The incidences of grades II to IV acute graft versus host disease (aGVHD) and of grades III and IV aGVHD were 28.8% (CI, 16.87–40.8%), and 14.2% (CI, 5.4–23.0%), respectively. The cumulative incidences for chronic GVHD (cGVHD) at 2 years after HSCT were 35.2% (CI, 21.2–49.2%). Up to April 30, 2013, 12 patients had relapsed and 11 died from relapse, and 37 patients were still alive without disease recurrence. The relapse and NRM rates at 3 years were 25.3% (CI, 12.7–37.9%) and 18.0% (CI, 2.6–33.4%), respectively. The probalities of overall survival and leukemia free survival were 61.8% (CI, 46.0–77.6%) and 56.3% (CI, 38.1–74.5%) at 3 years, respectively. Patients transplanted during their hematological first complete remission (CR1) had a lower relapse rate (17.9% vs. 48.1%, P = 0.03) compared with patients transplanted beyond CR1. The median overall survival for the 29 patients not receiving allo‐HSCT during the study period was 145 days from diagnosis. This study showed that allo‐HSCT could be a valuable treatment choice for MLL+ acute leukemia. Am. J. Hematol. 89:130–136, 2014. © 2013 Wiley Periodicals, Inc.
Oral and Dental Diseases: Aetiology, Histopathology, Clinical Features and Treatment: A Textbook for Dental Students and a Reference Book for Dental and Medical Practitioners
Authors: Hubert Horace Stones
Journal: JAMA (1949)

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Distinct platelet thromboxane A2/prostaglandin H2 receptor subtypes. A radioligand binding study of human platelets.
Authors: G W Dorn
Journal: Journal of Clinical Investigation (1989)

Thromboxane A2 (TXA2) and prostaglandin H2 (PGH2) may aggregate platelets via a common membrane receptor(s). To further characterize this receptor, binding of the radiolabeled TXA2/PGH2 mimetic [125I]BOP to washed human platelets (WP) was investigated. [125I]BOP was competitively displaced from its platelet binding site by stable TXA2/PGH2 analogues. Competition curves were shallow with Hill coefficients of -0.73 +/- 0.05 (P less than 0.001 different from unity) (90 +/- 1% specific binding). Scatchard plots were curvilinear and most consistent with two binding sites; a high-affinity site with Kd of 234 +/- 103 pM, Bmax of 0.7 +/- 0.3 pM/mg protein (180 +/- 87 sites/WP), and a lower affinity site with Kd of 2.31 +/- 0.86 nM, Bmax of 2.2 +/- 0.3 pM/mg protein (666 +/- 65 sites/WP). [125I]BOP association and dissociation kinetics gave a Kd of 157 pM without evidence of negative cooperativity. The EC50 for I-BOP-induced initial Ca2+ increase was 209 +/- 24 pM, shape change was 263 +/- 65 pM, and aggregation was 4.4 +/- 0.5 nM. Parallel binding studies using the TXA2/PGH2 receptor antagonist [125I]PTA-OH showed a single binding site. The rank order for TXA2/PGH2 analogues to displace [125I]PTA-OH was identical to that for [125I]BOP. These studies indicate that [125I]BOP binds to two distinct sites on human platelets that may represent platelet TXA2/PGH2 receptor subtypes. The close correlation of IC50 values for I-BOP-induced platelet shape change and aggregation with the two Kds for [125I]BOP binding suggests that these platelet responses may be independently mediated by the two putative receptors.