tbuckley/cabot-search huggingface dataset:
Parental Grief After Losing a Child to Cancer: Impact of Professional and Social Support on Long-Term Outcomes
Authors: Ulrika C. Kreicbergs, Patrizia Lannen, Erik Onelov, Joanne Wolfe
Journal: Journal of Clinical Oncology (2007)

It is still uncertain whether or not parents can ever come to terms with the loss of a child and whether professional or social support facilitate the long-term grief process.A Swedish population-based study, which sent an anonymous, mail-in questionnaire to parents who had lost a child to a malignancy 4 to 9 years earlier, gained the participation of 449 (80%) of 561 parents. Parents were asked whether, and to what extent, they had worked through their grief. Questions were also asked regarding those who provided parents with support. We examined candidate factors to determine their associations with greater likelihood of working through parental grief.Overall, most parents (74%) stated that they had worked through their grief "a lot" or "completely" at the time of the follow-up. Parents who had shared their problems with others during the child's illness (fathers: relative risk [RR], 3.0; 95% CI, 1.8 to 5.0; mothers: RR 1.9; 95% CI, 1.2 to 2.8) and who had access to psychological support during the last month of their child's life (fathers: RR 1.4; 95% CI, 1.0 to 1.8; mothers: RR 1.3; 95% CI, 1.1 to 1.6) were more likely to have worked through their grief. In cases where health care staff offered parents counseling during the child's last month, the parents were more likely to have worked through their grief (fathers: RR 1.5; 95% CI, 1.2 to 1.8; mothers; RR 1.2; 95% CI, 1.1 to 1.4).Most parents eventually work through the grief associated with losing a child to cancer. In the long term, sharing the emotional burden with others facilitates the grieving process.
Meta-Analysis of <i>BRCA1</i> and <i>BRCA2</i> Penetrance
Authors: Sining Chen, Giovanni Parmigiani
Journal: Journal of Clinical Oncology (2007)

Genetic counseling is now routinely offered to individuals at high risk of carrying a BRCA1 or BRCA2 mutation. Risk prediction provided by the counselor requires reliable estimates of the mutation penetrance. Such penetrance has been investigated by studies worldwide. The reported estimates vary. To facilitate clinical management and counseling of the at-risk population, we address this issue through a meta-analysis.We conducted a literature search on PubMed and selected studies that had nonoverlapping patient data, contained genotyping information, used statistical methods that account for the ascertainment, and reported risks in a useable format. We subsequently combined the published estimates using the DerSimonian and Laird random effects modeling approach.Ten studies were eligible under the selection criteria. Between-study heterogeneity was observed. Study population, mutation type, design, and estimation methods did not seem to be systematic sources of heterogeneity. Meta-analytic mean cumulative cancer risks for mutation carriers at age 70 years were as follows: breast cancer risk of 57% (95% CI, 47% to 66%) for BRCA1 and 49% (95% CI, 40% to 57%) for BRCA2 mutation carriers; and ovarian cancer risk of 40% (95% CI, 35% to 46%) for BRCA1 and 18% (95% CI, 13% to 23%) for BRCA2 mutation carriers. We also report the prospective risks of developing cancer for currently asymptomatic carriers.This article provides a set of risk estimates for BRCA1 and BRCA2 mutation carriers that can be used by counselors and clinicians who are interested in advising patients based on a comprehensive set of studies rather than one specific study.
Repeated TLR9 stimulation results in macrophage activation syndrome–like disease in mice
Authors: Edward M. Behrens, Scott W. Canna, Katharine Slade, Sheila Rao, Portia A. Kreiger, Michele Paessler, Taku Kambayashi, Gary A. Koretzky
Journal: Journal of Clinical Investigation (2011)

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are 2 similar diseases characterized by a cytokine storm, overwhelming inflammation, multiorgan dysfunction, and death. Animal models of HLH suggest that disease is driven by IFN-γ produced by CD8⁺ lymphocytes stimulated by persistent antigen exposure. In these models and patients with "primary" HLH, the antigen persists due to genetic defects, resulting in ineffective cytotoxic responses by CD8⁺ T cells and poor pathogen clearance. However, infectious triggers are often not identified in patients with MAS, and some patients with HLH or MAS lack defects in cytotoxic T cell killing. Herein, we show that repeated stimulation of TLR9 produced an HLH/MAS-like syndrome on a normal genetic background, without exogenous antigen. Like previous HLH models, TLR9-induced MAS was IFN-γ dependent; however, unlike other models, disease did not require lymphocytes. We further showed that IL-10 played a protective role in this model and that blocking IL-10 signaling led to the development of hemophagocytosis. IL-10 may therefore be an important target for the development of effective therapeutics for MAS. Our data provide insight into MAS-like syndromes in patients with inflammatory diseases in which there is chronic innate immune activation but no genetic defects in cytotoxic cell function.
PMO-123 Gene transfer of dimethylarginine dimethylaminohydrolase-1 reduces portal pressure in a rodent model of cirrhosis
Authors: G Mehta, V Sharma, A Habtesion, V Balasubramaniyan, N A Davies, R Jalan, V Budhram-Mahadeo, R P Mookerjee
Journal: Gut (2012)

<h3>Introduction</h3> Portal hypertensive bleeding is a grave complication of cirrhosis. Asymmetric dimethylarginine (ADMA), an endogenous eNOS inhibitor, is elevated in cirrhosis, relates to degree of portal hypertension, and is prognostic in acute-on-chronic liver failure. Dimethylarginine-dimethylaminohydrolase-1 (DDAH-1), a key enzyme metabolising hepatic ADMA, is reduced in cirrhosis. Therapies which indirectly increase hepatic DDAH-1, such as anti-TNFα therapy or FXR agonists, lead to reduced hepatic ADMA, increased NO and lowered portal pressure. Therefore, there is accumulating evidence for DDAH-1 as a therapeutic target, but specific evidence for DDAH-1 reconstitution is lacking. The aim of this study was to adopt a DDAH-1 gene therapy strategy in portal hypertension. <h3>Methods</h3> Hydrodynamic injection leads to hepatic gene transduction by causing turbulent, retrograde venous flow, permeation of hepatic parenchymal cells and consequent plasmid expression. Human DDAH-1 cDNA was cloned into the pCMV-Sport6 expression plasmid. Sprague-dawley rats (n=9) underwent bile duct-ligation, and after 4 weeks were injected with 800 μg of either pCMV-Sport6-DDAH1 (n=5) or non-expressing control plasmid (n=4). After 72 h, rats underwent direct portal pressure assessment under anaesthesia and were then sacrificed. Plasma ALT was measured by Cobas-Integra analyser. Transgene expression was measured by quantitative PCR, with Taqman probes specific for human DDAH-1 to distinguish rodent DDAH-1. Protein expression was measured by western blot. <h3>Results</h3> Highly effective gene transfer (between 20 and 120-fold increase) of human DDAH-1 was seen in 3 out of 5 treated animals. None of the animals treated with control plasmid expressed human DDAH-1. The three “responders” to gene therapy also had highly significantly increased DDAH-1 protein expression compared with “non-responders” or controls (p&lt;0.05). There was no difference in ALT between the groups. Portal pressure was significantly lower in “responders” to gene therapy than “non-responders” or animals treated with control plasmid (p&lt;0.05). <h3>Conclusion</h3> This study demonstrates that DDAH-1 is a specific molecular target for portal pressure reduction. Hydrodynamic injection is variable in efficiency of gene delivery due to the nature of the technique. However, despite these limitations, this study clearly shows proof of concept for efficient vector-based DDAH-1 gene therapy in lowering portal pressure and preventing bleeding in cirrhosis. <h3>Competing interests</h3> None declared.
Sequential genotyping of<i>Pseudomonas aeruginosa</i>from upper and lower airways of cystic fibrosis patients
Authors: A. Jung, I. Kleinau, G. Schönian, A. Bauernfeind, C. Chen, M. Griese, G. Döring, U. Göbel, U. Wahn, K. Paul
Journal: European Respiratory Journal (2002)

A controversy exists concerning the adequate specimen to characterise colonisation of cystic fibrosis (CF) airways by Pseudomonas aeruginosa . Oropharyngeal, sputum and bronchoalveolar lavage samples were evaluated from 38 stable CF patients for the detection of P. aeruginosa , genetically different isolates within the same host and longitudinal variations in the genotype during repeated examinations. Bacterial isolates were typed by pulsed-field gel electrophoresis of deoxyribonucleic acid macrorestriction fragments. Sensitivity, negative and positive predictive values and specificity to detect P. aeruginosa were 35.7, 73.5, 83.3 and 96.2% for oropharyngeal cultures in nonexpectorating patients and 91.7, 94.1, 100 and 100% for sputum cultures from expectorating patients, respectively. Genotypes of Pseudomonas isolates recovered from oropharyngeal swabs and sputum differed to the strains recovered by bronchoscopy in 55% and 40%, respectively. In 62% longitudinal variations in the genotype occurred. One-half of these alterations were detectable by bronchoscopy only. In conclusion, sputum samples were of equal value as specimens from bronchoalveolar lavage to detect Pseudomonas aeruginosa colonisation. Cultures from the oropharynx are not suitable for characterising bacterial conditions in the cystic fibrosis lung. Different genotypes within the same host and longitudinal genetic alterations are common and may be detectable in the bronchoalveolar lavage fluid exclusively.
The electrophysiologic effects of low and high digoxin concentrations on isolated mammalian cardiac tissue: reversal by digoxin-specific antibody
Authors: William J. Mandel, J. Thomas Bigger, Vincent P. Butler
Journal: Journal of Clinical Investigation (1972)

The effects of digoxin on electrophysiologic properties were evaluated in isolated perfused cardiac tissue. In canine Purkinje fiber (PF)-ventricular muscle (VM) preparations, control measurements, using microelectrode technique, were made of: resting potential (RP), action potential (AP) amplitude, rate of rise, overshoot, duration (APD), membrane responsiveness, conduction velocity (CV), and refractory period. The preparation was then exposed to 1 x 10(-7) M digoxin and repeat measurements were carried out every 15 min. At slow (30/min) rates of stimulation APD initially prolonged then markedly shortened. With more rapid stimulation (75 and 120/min) no initial APD prolongation was observed. When stimulated at 75/min, RP and AP rate of rise, amplitude, and CV remained near control values for 60-75 min then rapidly decreased until electrical inexcitability (110+/-15 min). At that time fibers were perfused with serum containing digoxin-specific antibody (DSA) or one of a group of test solutions. In the preparations exposed to DSA, membrane characteristics improved by 15 min, and by 60 min approximated control values. No beneficial effect was seen with the various test solutions. DSA also reversed digoxin-induced enhanced phase 4 depolarization in PF. Effective (ERP) and Functional (FRP) refractory periods of rabbit atrioventricular (AV) node preparations were measured in the control state. The tissue was then exposed to 1 x 10(-7) M digoxin and refractory period measurements repeated. At a time when AV conduction prolonged by 20%, associated with marked prolongation of ERP and FRP, DSA or various test solutions were perfused. The prolongation in ERP, FRP, and AV conduction time rapidly returned to normal only in the DSA perfused tissue. It is concluded that DSA has the ability to reverse pronounced toxic electrophysiological effects of digoxin in in vitro cardiac tissue.
Evaluation of the contribution of cumulative levels of inflammation to the variance in joint destruction in rheumatoid arthritis
Authors: Rachel Knevel, Jessica Annemarie Bernadette van Nies, S le Cessie, Tom W J Huizinga, E Brouwer, Annette H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2012)

In rheumatoid arthritis (RA) inflammation causes joint destruction,1–3 but disconnection between inflammation and destruction has also been described.4–10 Although several studies have evaluated the relation between inflammation and destruction, it has never been quantified to what proportion the variance in joint destruction is accounted for by cumulative doses of inflammation. Therefore, we evaluated the variance in severity of joint destruction on hands and feet radiographs after 5 years of disease (Sharp-van-der-Heijde method, SHS) that is contributed by a cumulative dose of inflammation over this period. Ethical approval was obtained from the local ethical committee and all included patients gave their informed consent.

The cumulative inflammatory burden was estimated using the area under the curve of 3-monthly measured C reactive protein levels (AUCCRP). First, 278 RA patients (1987 ACR criteria) with 2692 CRP measurements and with radiographs at 5-year follow-up of the Leiden Early-Arthritis-Clinic10 were studied. Second, 911 CRP measurements obtained from 74 Groningen11 RA patients with radiographs at 4, 5, 6 or 7 years follow-up (depending on the availability of the radiographs) were studied as replication cohort. This study period was chosen since a substantial number of Groningen patients had no radiograph exactly …
Extracorporeal Cardiac Shock Wave Therapy Markedly Ameliorates Ischemia-Induced Myocardial Dysfunction in Pigs in Vivo
Authors: Takahiro Nishida, Hiroaki Shimokawa, Keiji Oi, Hideki Tatewaki, Toyokazu Uwatoku, Kohtaro Abe, Yasuharu Matsumoto, Noriyoshi Kajihara, Masataka Eto, Takehisa Matsuda, Hisataka Yasui, Akira Takeshita, Kenji Sunagawa
Journal: Circulation (2004)

Background— Prognosis of ischemic cardiomyopathy still remains poor because of the lack of effective treatments. To develop a noninvasive therapy for the disorder, we examined the in vitro and vivo effects of extracorporeal shock wave (SW) that could enhance angiogenesis. Methods and Results— SW treatment applied to cultured human umbilical vein endothelial cells significantly upregulated mRNA expression of vascular endothelial growth factor and its receptor Flt-1 in vitro. A porcine model of chronic myocardial ischemia was made by placing an ameroid constrictor at the proximal segment of the left circumflex coronary artery, which gradually induced a total occlusion of the artery with sustained myocardial dysfunction but without myocardial infarction in 4 weeks. Thereafter, extracorporeal SW therapy to the ischemic myocardial region (200 shots/spot for 9 spots at 0.09 mJ/mm 2 ) was performed (n=8), which induced a complete recovery of left ventricular ejection fraction (51±2% to 62±2%), wall thickening fraction (13±3% to 30±3%), and regional myocardial blood flow (1.0±0.2 to 1.4±0.3 mL · min −1 · g −1 ) of the ischemic region in 4 weeks (all P &lt;0.01). By contrast, animals that did not receive the therapy (n=8) had sustained myocardial dysfunction (left ventricular ejection fraction, 48±3% to 48±1%; wall thickening fraction, 13±2% to 9±2%) and regional myocardial blood flow (1.0±0.3 to 0.6±0.1 mL · min −1 · g −1 ). Neither arrhythmias nor other complications were observed during or after the treatment. SW treatment of the ischemic myocardium significantly upregulated vascular endothelial growth factor expression in vivo. Conclusions— These results suggest that extracorporeal cardiac SW therapy is an effective and noninvasive therapeutic strategy for ischemic heart disease.
An Epidemiologic and Genomic Investigation Into the Obesity Paradox in Renal Cell Carcinoma
Authors: A. Ari Hakimi, Helena Furberg, Emily C. Zabor, Anders Jacobsen, Nikolaus Schultz, Giovanni Ciriello, Nina Mikklineni, Brandon Fiegoli, Philip H. Kim, Martin H. Voss, Hui Shen, Peter W. Laird, Chris Sander, Victor E. Reuter, Robert J. Motzer, James J. Hsieh, Paul Russo
Journal: JNCI Journal of the National Cancer Institute (2013)

Obesity increases risk for clear-cell renal cell carcinoma (ccRCC), yet obese patients appear to experience longer survival than nonobese patients. We examined body mass index (BMI) in relation to stage, grade, and cancer-specific mortality (CSM) while considering detection bias, nutritional status, and molecular tumor features. Data were available from 2119 ccRCC patients who underwent renal mass surgery at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Logistic regression models produced associations between BMI and advanced disease. Multivariable competing risks regression models estimated associations between BMI and CSM. Somatic mutation, copy number, methylation, and expression data were examined by BMI among a subset of 126 patients who participated in the Cancer Genome Atlas Project for ccRCC using the Kruskal–Wallis or Fisher exact tests. All statistical tests were two-sided. Obese and overweight patients were less likely to present with advanced-stage disease compared with normal-weight patients (odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.48 to 0.79 vs OR = 0.65, 95% CI = 0.51 to 0.83, respectively). Higher BMI was associated with reduced CSM in univariable analyses ( P < .005). It remained statistically significant after adjustment for comorbidities and albumin level, but it became non-statistically significant after adjusting for stage and grade ( P > .10). Genome-wide interrogation by BMI suggested differences in gene expression of metabolic and fatty acid genes, including fatty acid synthase (FASN), consistent with the obesity paradox. Our findings suggest that although BMI is not an independent prognostic factor for CSM after controlling for stage and grade, tumors developing in an obesogenic environment may be more indolent.
STUDIES ON THE GENERALIZED SHWARTZMAN REACTION
Authors: Robert A. Good, Lewis Thomas
Journal: The Journal of Experimental Medicine (1952)

Intravenous injection of thorotrast or trypan blue rendered rabbits susceptible to the production of bilateral cortical necrosis of the kidneys by a single intravenous injection of small amounts of meningococcal or Serratia marcescens toxin. This reaction was not produced when thorotrast or trypan blue were injected after toxin had been given. A single intradermal injection of toxin produced hemorrhagic skin lesions resembling the local Shwartzman reaction in rabbits given thorotrast 6 hours previously. These animals also developed bilateral cortical necrosis of the kidneys. When the order of injection was reversed, and thorotrast given after toxin, neither skin nor kidney lesions occurred. The skin and kidney lesions in thorotrast-treated rabbits were, like the local and generalized Shwartzman reactions, completely prevented by treatment with nitrogen mustard, in doses sufficient to produce polymorphonuclear leukopenia. The significance of these reactions, and their relationship to the previously described response to toxin in cortisone-treated rabbits, are discussed.
International Union of Pharmacology. XXXIV. Lysophospholipid Receptor Nomenclature
Authors: J. Chun
Journal: Pharmacological Reviews (2002)

The lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are now recognized as important extracellular signaling molecules. These lipid mediators are pleiotropic; among the most common cellular responses are mitogenesis, cell survival (anti-apoptosis), inhibition of adenylyl cyclase and calcium mobilization. Physiologic events associated with these mediators include platelet aggregation, vasopressor activity, wound healing, immune modulation, and angiogenesis. Many of the actions of LPA and S1P are mediated through a set of eight G protein-coupled receptors. Five of these are S1P-prefering while the remaining three are LPA receptors. These receptors are expressed widely and in aggregate signal through a variety of heterotrimeric G proteins. The lysophospholipid receptor family is referred to commonly as the "Edg" group (e.g., Edg-1, Edg-2, etc.). Herein, the molecular pharmacology of the lysophospholipid receptors is reviewed briefly, and a rational nomenclature for LPA and S1P receptors that is consistent with the International Union of Pharmacology guidelines is proposed.
Treatment of relapse of small cell lung cancer in selected patients with the initial combination chemotherapy with carboplatin, etoposide and epirubicin.
Authors: C R Nyman
Journal: Thorax (1992)

Cellular mechanisms of acute lung injury: implications for future treatment in the adult respiratory distress syndrome Although I agree that antibodies to adhesive molecules will have a role in treating the adult respiratory distress syndrome (ARDS), as neutrophil activation by C5a forms the basis of the injury I cannot understand why Drs S C Donnelly and C Haslett (April 1992;47: 260-3) fail to give credit to the overriding importance of endotoxaemia.Since there are so many mechanisms and mediators con- cerned in ARDS, just as there are in Gram negative bacterial shock, there has to be a common trigger-that is, usually, lipopoly- saccharide (cf fig 2).It seems that mistrust has arisen from the results of two sets of experiments conducted by Haslett et al, in particular the one in which a synergistic effect of a small dose of lipopoly- saccharide and C5a was seen.Yet in fact endotoxin itself produces C5a.In my ex- periments conducted in 1970-72 it was clear that endotoxin caused acute lung injury with all the features of ARDS.The details of the mechanisms were reviewed by Brigham and Meyrick' in 1986.In recent years several groups have described endotoxaemia at the onset of ARDS.'4Thus I feel sure that the emphasis will switch to means of combating endotoxaemia.
Effect of Exercise on Total and Intra-abdominal Body Fat in Postmenopausal Women
Authors: Melinda L. Irwin, Yutaka Yasui, Cornelia M. Ulrich, Deborah Bowen, Rebecca E. Rudolph, Robert S. Schwartz, Michi Yukawa, Erin Aiello, John D. Potter, Anne McTiernan
Journal: JAMA (2003)

<h3>Context</h3> The increasing prevalence of obesity is a major public health concern. Physical activity may promote weight and body fat loss. <h3>Objective</h3> To examine the effects of exercise on total and intra-abdominal body fat overall and by level of exercise. <h3>Design</h3> Randomized controlled trial conducted from 1997 to 2001. <h3>Setting and Participants</h3> A total of 173 sedentary, overweight (body mass index ≥24.0 and &gt;33% body fat), postmenopausal women aged 50 to 75 years who were living in the Seattle, Wash, area. <h3>Intervention</h3> Participants were randomly assigned to an intervention consisting of exercise facility and home-based moderate-intensity exercise (n = 87) or a stretching control group (n = 86). <h3>Main Outcome Measure</h3> Changes in body weight and waist and hip circumferences at 3 and 12 months; total body, intra-abdominal, and subcutaneous abdominal fat at 12 months. <h3>Results</h3> Twelve-month data were available for 168 women. Women in the exercise group participated in moderate-intensity sports/recreational activity for a mean (SD) of 3.5 (1.2) d/wk for 176 (91) min/wk. Walking was the most frequently reported activity. Exercisers showed statistically significant differences from controls in baseline to 12-month changes in body weight (–1.4 kg; 95% confidence interval [CI], –2.5 to –0.3 kg), total body fat (–1.0%; 95% CI, –1.6% to –0.4%), intra-abdominal fat (–8.6 g/cm<sup>2</sup>; 95% CI, –17.8 to 0.9 g/cm<sup>2</sup>), and subcutaneous abdominal fat (–28.8 g/cm<sup>2</sup>; 95% CI, –47.5 to –10.0 g/cm<sup>2</sup>). A significant dose response for greater body fat loss was observed with increasing duration of exercise. <h3>Conclusions</h3> Regular exercise such as brisk walking results in reduced body weight and body fat among overweight and obese postmenopausal women.