tbuckley/cabot-search huggingface dataset:
SIRT1 and AMPK Mediate Hypoxia-Induced Resistance of Non–Small Cell Lung Cancers to Cisplatin and Doxorubicin
Authors: Dong Hoon Shin, Yong-Joon Choi, Jong-Wan Park
Journal: Cancer Research (2013)

SIRT1 is an NAD(+)-dependent protein deacetylase induced by metabolic stresses, such as nutrition or oxygen deprivation. Although SIRT1 contributes to aging and metabolic disorders, its role in cancer progression and therapeutic responses remains controversial. Because hypoxia occurs widely in solid tumors, where it provokes drug resistance, we investigated the involvement of SIRT1 in hypoxia-induced chemoresistance. SIRT1 was downregulated in a panel of non-small cell lung carcinoma (NSCLC) cells exposed to hypoxia for 48 hours. The master metabolic kinase AMP-activated protein kinase (AMPK) was inactivated under the same conditions, likely due to attenuation of the SIRT1/LKB1-mediated AMPK activation process. Notably, hypoxic inactivation of this SIRT1-AMPK pathway led to cisplatin and doxorubicin resistance. Mechanistic investigations suggested that this pathway supported the cytotoxic response to cisplatin and doxorubicin by licensing an apoptotic process controlled by mitochondria. We confirmed the involvement of this pathway in a mouse xenograft model of human NSCLC. Furthermore, we demonstrated that a SIRT1 activator SRT1720 augmented the antitumor effects of cisplatin, and these effects could be blocked by administration of an AMPK inhibitor compound C. Taken together, our results offer preclinical proof-of-concept to target the SIRT1-AMPK pathway as a strategy to overcome hypoxia-induced chemoresistance in NSCLC.
Safety of 2 Months of Rifampin and Pyrazinamide for Treatment of Latent Tuberculosis
Authors: Jason E. Stout, John J. Engemann, Allen C. Cheng, Ellen R. Fortenberry, Carol D. Hamilton
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

An alternative regimen for the treatment of latent tuberculosis infection is 2 months of rifampin and pyrazinamide, but some patients have died of hepatitis associated with this therapy. One hundred fourteen patients received rifampin/pyrazinamide in Wake County, North Carolina, between December 1999 and May 2002; 60.5% of these patients were homeless, and at least 17% drank alcohol to excess. Seventy-seven patients (67.5%) completed a full 2-month course. Nine patients had a history of viral hepatitis or chronic liver disease. Four of 114 (3.5%; 95% confidence interval, 1.0-8.7%) patients developed hepatitis on therapy, and another two had symptoms consistent with hepatitis but did not report for laboratory testing (total confirmed plus suspected hepatitis rate 5.3%; 95% confidence interval, 2.0-11.1%). No patient who developed hepatitis had a history of viral hepatitis or liver disease, and none had been previously treated with isoniazid. No patients died or were hospitalized due to drug side effects. Rifampin/pyrazinamide was associated with a significantly higher rate of hepatitis than previously described with isoniazid therapy for latent tuberculosis but resulted in a high completion rate. The rifampin/pyrazinamide regimen for latent tuberculosis infection may be useful for high-risk, traditionally nonadherent patient groups, but careful monitoring for toxicity is required.
The Physiologic Effect of Contrast Media Used for Angiocardiography
Authors: GEORGE G. ROWE, JOHN H. HUSTON, H. TUCHMAN, GEORGE M. MAXWELL, ARVIN B. WEINSTEIN, CHARLES W. CRUMPTON
Journal: Circulation (1956)

The deaths from angiocardiography at Wisconsin General Hospital were reviewed and found to be two per cent of 249 patients. These 5 deaths are reported briefly. Investigation was carried out to determine the hemodynamic effects of contrast substances on 12 dogs. In general, there was a temporary increase in right atrial and pulmonary arterial pressure followed by a rather marked decrease in systemic arterial pressure and tachycardia. The significance of these findings is discussed in relation to shunts within the heart or between the aorta and pulmonary artery.
Coronary Artery Bypass Grafting vs Percutaneous Coronary Intervention and Long-term Mortality and Morbidity in Multivessel Disease
Authors: Ilke Sipahi, M. Hakan Akay, Sinan Dagdelen, Arie Blitz, Cem Alhan
Journal: JAMA Internal Medicine (2013)

Recent trials of percutaneous coronary intervention (PCI) vs coronary artery bypass grafting (CABG) for multivessel disease were not designed to detect a difference in mortality and therefore were underpowered for this outcome. Consequently, the comparative effects of these 2 revascularization methods on long-term mortality are still unclear. In the absence of solid evidence for mortality difference, PCI is oftentimes preferred over CABG in these patients, given its less invasive nature.To determine the comparative effects of CABG vs PCI on long-term mortality and morbidity by performing a meta-analysis of all randomized clinical trials of the current era that compared the 2 treatment techniques in patients with multivessel disease.A systematic literature search was conducted for all randomized clinical trials directly comparing CABG with PCI.To reflect current practice, we included randomized trials with 1 or more arterial grafts used in at least 90%, and 1 or more stents used in at least 70% of the cases that reported outcomes in patients with multivessel disease.Numbers of events at the longest possible follow-up and sample sizes were extracted.A total of 6 randomized trials enrolling a total of 6055 patients were included, with a weighted average follow-up of 4.1 years. There was a significant reduction in total mortality with CABG compared with PCI (I2 = 0%; risk ratio [RR], 0.73 [95% CI, 0.62-0.86]) (P < .001). There were also significant reductions in myocardial infarction (I2 = 8.02%; RR, 0.58 [95% CI, 0.48-0.72]) (P < .001) and repeat revascularization (I2 = 75.6%; RR, 0.29 [95% CI, 0.21-0.41]) (P < .001) with CABG. There was a trend toward excess strokes with CABG (I2 = 24.9%; RR, 1.36 [95% CI, 0.99-1.86]), but this was not statistically significant (P = .06). For reduction in total mortality, there was no heterogeneity between trials that were limited to and not limited to patients with diabetes or whether stents were drug eluting or not. Owing to lack of individual patient-level data, additional subgroup analyses could not be performed.In patients with multivessel coronary disease, compared with PCI, CABG leads to an unequivocal reduction in long-term mortality and myocardial infarctions and to reductions in repeat revascularizations, regardless of whether patients are diabetic or not. These findings have implications for management of such patients.
Endocannabinoid signalling as an anti-inflammatory therapeutic target in atherosclerosis: does it work?
Authors: S. Immenschuh
Journal: Cardiovascular Research (2009)

The endocannabinoid system is a physiological signalling network that has attracted major attention in recent years because of its therapeutic potential for the treatment of various pathological conditions, including cardiovascular disease. More specifically, targeted modulation of the major receptors of this system, the G-protein-coupled cannabinoid 1 (CB1) and cannabinoid 2 (CB2) receptors, has been implicated in the protection against atherosclerosis. Accumulating evidence suggests that specific blockage of these receptors may have beneficial effects on classical cardiovascular risk factors such as hypercholesterolaemia, obesity, and impaired glucose tolerance.1 In a pioneering report, it was demonstrated that low levels of the cannabinoid derivative delta-9-tetrahydrocannabinoid reduced the progression of atherosclerosis in an apolipoprotein E knockout mouse model of established atherosclerosis via the CB2 receptor. This protective effect has been shown to be mediated via the immunomodulatory, anti-inflammatory actions of this receptor.2 Subsequently, CB2 receptor-dependent anti-inflammatory therapeutic effects have also been observed in other conditions such as sepsis.3 More recently, the CB1 receptor antagonist rimonabant (SR141716) has been shown to provide anti-inflammatory protection against atherosclerosis.4 Since the majority of these studies have been performed in mouse models, the relevance of the findings for humans has remained largely elusive. Moreover, the regulatory role of cannabinoid signalling for specific interactions of immune cells with the vascular system … 

*Corresponding author. Tel: +49 511 532 6704/9714; fax: +49 511 532 2079. E-mail address : immenschuh.stephan{at}mh-hannover.de
One born every minute
Authors: L. Farrell
Journal: BMJ (1997)

You can fool some of the people some of the time, but you can't fool all of the people all of the time (Abraham Lincoln).

You can fool doctors all of the time (Liam Farrell).

General practice is daily becoming more and more of a dumping ground. I received a call recently to an elderly man who had fallen.

“Put him into bed and I'll come down and check he's all right,” I advised.

“But, Doctor,” came the reply, “he'll need to be lifted.”

“No problem,” said I, still not understanding, “just make him comfortable in bed and I'll be …
Baseline faecal occult blood concentration as a predictor of incident colorectal neoplasia: longitudinal follow-up of a Taiwanese population-based colorectal cancer screening cohort
Authors: Li-Sheng Chen, Amy Ming-Fang Yen, Sherry Yueh-Hsia Chiu, Chao-Sheng Liao, Hsiu-Hsi Chen
Journal: The Lancet Oncology (2011)
A molecular view of primate phylogeny and important systematic and evolutionary questions.
Authors: B F Koop, D A Tagle, M Goodman, J L Slightom
Journal: Molecular Biology and Evolution (1989)

Phylogenetic analysis of extensive nucleotide sequence data from primate beta-globin gene clusters elucidates the systematics and evolution of the order Primates and reveals that rates of accumulation of mutations vary by as much as a factor of seven among different primate lineages. The picture of primate phylogeny from DNA sequences clarifies many ambiguities of the morphological picture. In the molecular picture, dwarf and brown lemurs group together into superfamily Lemuroidea, Lemuroidea and Lorisoidea into suborder Strepsirhini, and Tarsius and Anthropoidea into suborder Haplorhini. The molecular picture also provides both significant evidence for a human-chimpanzee clade that narrowly excludes gorilla and overwhelming evidence for the gorilla-chimpanzee-human clade within Hominoidea. Rates of DNA sequence evolution appear to have been fastest in the early primates ancestral to Anthropoidea and next fastest on the lorisoid branch. Rates were slowest over the past 25 Myr of hominoid descent, suggesting that mechanisms lowering the mutation rate evolved in correlation with lengthened life spans.
A gene-environment interaction between HLA SE alleles and smoking affects the reactivity of ACPA to various citrullinated antigens
Authors: D van der Woude, W G Alemayehu, N A Daha, W Verduyn, R R P de Vries, J J Houwing-Duistermaat, T W J Huizinga, R E M Toes
Journal: Annals of the Rheumatic Diseases (2010)

Objective It has recently been postulated that a specifi c interaction exists between genotype, smoking and autoimmunity to citrullinated α-enolase peptide (CEP-1), and that therefore, the major genetic and environmental susceptibility factors for RA are mainly associated with the development of anti-CEP1positive disease.It is unclear however, if this interaction is truly specifi c for citrullinated α-enolase.Methods The reactivity of 745 RA patients to cyclic citrullinated peptide and to two citrullinated peptides derived from vimentin (cVim) and fi brinogen (cFib) was determined by ELISA.The separate effects of the human leucocyte antigen shared epitope (HLA SE) alleles and smoking were assessed by logistic regression analysis.Biologic interaction was analysed by investigating if the effects of the risk factors combined exhibited departure from additivity. ResultsThe ACPA reactivity profi le was affected by a signifi cant biological interaction between the HLA SE alleles and smoking.Both the separate effects of HLA SE alleles and on August 14, 2023 by guest.
Personality Diagnoses in Adolescence: DSM-IV Axis II Diagnoses and an Empirically Derived Alternative
Authors: Drew Westen, Jonathan Shedler, Christine Durrett, Samantha Glass, Andy Martens
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: The study of personality pathology in adolescence is in its infancy. This article examined the applicability and limits of DSM-IV axis II personality disorder diagnoses in adolescents, assessed the validity of a method for assessing adolescent personality pathology, and began to develop an empirically grounded classification. METHOD: A total of 296 randomly selected clinicians described a patient age 14–18 in treatment for maladaptive personality patterns using axis II ratings scales and the Shedler-Westen Assessment Procedure–200 for Adolescents (SWAP-200-A), a Q-sort instrument for assessing adolescent personality pathology. After examining the nature and frequency of axis II disorders in the sample, the authors used Q-factor analysis to identify naturally occurring groupings of patients on the basis of shared personality features. RESULTS: Axis II diagnoses in adolescents resembled those in adults, although application of DSM-IV criteria appeared to overdiagnose antisocial and avoidant personality disorder in adolescents. Q analysis with the SWAP-200-A isolated five personality disorders (antisocial-psychopathic, emotionally dysregulated, avoidant-constricted, narcissistic, and histrionic) and one personality style. Patients’ dimensional scores on each diagnostic prototype showed predictable associations with ratings of current axis II disorders, measures of adaptive functioning, and symptoms assessed with the Child Behavior Checklist. CONCLUSIONS: With some exceptions, personality pathology in adolescence resembles that in adults and is diagnosable in adolescents ages 14–18. Categories and criteria developed for adults may not be the optimal way of diagnosing adolescents. Data from samples of adolescents may prove useful in developing an empirically and clinically grounded classification of personality pathology in adolescents.
Ovarian relapse in a young woman with acute lymphoblastic leukaemia
Authors: David C. Heaton, Gerald B. Duff
Journal: American Journal of Hematology (1989)

Abstract Bilateral ovarian relapse in a young woman with acute lymphoblastic leukaemia (ALL) was treated by oophorectomy and intensive chemotherapy. She remains well off therapy 97 months following diagnosis and 45 months from ovarian relapse.
Gastric aspirate culture using the microscopic observation drug susceptibility (MODS) technique is superior to other methods for bacteriological confirmation of tuberculosis in children
Authors: J. E. Ho
Journal: Thorax (2010)

Bacteriological evidence of tuberculosis in children is difficult to obtain and is not found in the majority of clinically suspected cases. In this study, which was conducted in Peru, gastric aspirates, nasopharyngeal aspirates and stool samples were taken from 218 children with clinically suspected tuberculosis and nasopharyngeal aspirates and stool samples were taken from 238 low-risk controls. These were …
Disability weights for the Global Burden of Disease 2013 study
Authors: Joshua A Salomon, Juanita A Haagsma, Adrian Davis, Charline Maertens de Noordhout, Suzanne Polinder, Arie H Havelaar, Alessandro Cassini, Brecht Devleesschauwer, Mirjam Kretzschmar, Niko Speybroeck, Christopher J L Murray, Theo Vos
Journal: The Lancet Global Health (2015)

The Global Burden of Disease (GBD) study assesses health losses from diseases, injuries, and risk factors using disability-adjusted life-years, which need a set of disability weights to quantify health levels associated with non-fatal outcomes. The objective of this study was to estimate disability weights for the GBD 2013 study.We analysed data from new web-based surveys of participants aged 18-65 years, completed in four European countries (Hungary, Italy, the Netherlands, and Sweden) between Sept 23, 2013, and Nov 11, 2013, combined with data previously collected in the GBD 2010 disability weights measurement study. Surveys used paired comparison questions for which respondents considered two hypothetical individuals with different health states and specified which person they deemed healthier than the other. These surveys covered 183 health states pertinent to GBD 2013; of these states, 30 were presented with descriptions revised from previous versions and 18 were new to GBD 2013. We analysed paired comparison data using probit regression analysis and rescaled results to disability weight units between 0 (no loss of health) and 1 (loss equivalent to death). We compared results with previous estimates, and an additional analysis examined sensitivity of paired comparison responses to duration of hypothetical health states.The total analysis sample consisted of 30 230 respondents from the GBD 2010 surveys and 30 660 from the new European surveys. For health states common to GBD 2010 and GBD 2013, results were highly correlated overall (Pearson's r 0·992 [95% uncertainty interval 0·989-0·994]). For health state descriptions that were revised for this study, resulting disability weights were substantially different for a subset of these weights, including those related to hearing loss (eg, complete hearing loss: GBD 2010 0·033 [0·020-0·052]; GBD 2013 0·215 [0·144-0·307]) and treated spinal cord lesions (below the neck: GBD 2010 0·047 [0·028-0·072]; GBD 2013 0·296 [0·198-0·414]; neck level: GBD 2010 0·369 [0·243-0·513]; GBD 2013 0·589 [0·415-0·748]). Survey responses to paired comparison questions were insensitive to whether the comparisons were framed in terms of temporary or chronic outcomes (Pearson's r 0·981 [0·973-0·987]).This study substantially expands the empirical basis for assessment of non-fatal outcomes in the GBD study. Findings from this study substantiate the notion that disability weights are sensitive to particular details in descriptions of health states, but robust to duration of outcomes.European Centre for Disease Prevention and Control, Bill and Melinda Gates Foundation.
Fasting and 2-Hour Plasma Glucose and Insulin
Authors: Ingrid M. Libman, Emma Barinas-Mitchell, Andrea Bartucci, Diego Chaves-Gnecco, Robert Robertson, Silva Arslanian
Journal: Diabetes Care (2010)

OBJECTIVE To determine whether elevated fasting or 2-h plasma glucose and/or insulin better reflects the presence of cardiovascular disease (CVD) risk markers in an overweight pediatric population with normal glucose tolerance. RESEARCH DESIGN AND METHODS A total of 151 overweight youths (8–17 years old) were evaluated with oral glucose tolerance tests and measurement of CVD risk factors. The study population was categorized according to quartiles of fasting and 2-h glucose and insulin levels. ANCOVA, adjusted for age, sex, race, Tanner stage, and percent body fat (measured by dual-energy X-ray absorptiometry), was used to compare metabolic variables between the quartiles of glucose and insulin groups. RESULTS Increasing quartiles of fasting and 2-h insulin were associated with increasing CVD risk factors. Glucose quartiles on the other hand, either fasting or at 2 h, were not. CONCLUSIONS These data suggest that hyperinsulinemia may be the earliest and/or primary metabolic alteration in childhood associated with risk markers for CVD. Prospective studies are needed.
Seeing is not (necessarily) believing
Authors: Virginia Slaughter, Linda Mealey
Journal: Behavioral and Brain Sciences (1998)

We doubt that theory of mind can be sufficiently demonstrated without reliance on verbal tests. Where language is the major tool of social manipulation, an effective theory of mind must use language as an input. We suspect, therefore, that in this context, prelinguistic human and nonhuman minds are more alike than are human pre- and postlinguistic minds.
An AICD-based functional screen to identify APP metabolism regulators
Authors: Can Zhang, Preeti J Khandelwal, Ranjita Chakraborty, Trinna L Cuellar, Srikant Sarangi, Shyam A Patel, Christopher P Cosentino, Michael O'Connor, Jeremy C Lee, Rudolph E Tanzi, Aleister J Saunders
Journal: Molecular Neurodegeneration (2007)

A central event in Alzheimer's disease (AD) is the regulated intramembraneous proteolysis of the beta-amyloid precursor protein (APP), to generate the beta-amyloid (Abeta) peptide and the APP intracellular domain (AICD). Abeta is the major component of amyloid plaques and AICD displays transcriptional activation properties. We have taken advantage of AICD transactivation properties to develop a genetic screen to identify regulators of APP metabolism. This screen relies on an APP-Gal4 fusion protein, which upon normal proteolysis, produces AICD-Gal4. Production of AICD-Gal4 induces Gal4-UAS driven luciferase expression. Therefore, when regulators of APP metabolism are modulated, luciferase expression is altered.To validate this experimental approach we modulated alpha-, beta-, and gamma-secretase levels and activities. Changes in AICD-Gal4 levels as measured by Western blot analysis were strongly and significantly correlated to the observed changes in AICD-Gal4 mediated luciferase activity. To determine if a known regulator of APP trafficking/maturation and Presenilin1 endoproteolysis could be detected using the AICD-Gal4 mediated luciferase assay, we knocked-down Ubiquilin 1 and observed decreased luciferase activity. We confirmed that Ubiquilin 1 modulated AICD-Gal4 levels by Western blot analysis and also observed that Ubiquilin 1 modulated total APP levels, the ratio of mature to immature APP, as well as PS1 endoproteolysis.Taken together, we have shown that this screen can identify known APP metabolism regulators that control proteolysis, intracellular trafficking, maturation and levels of APP and its proteolytic products. We demonstrate for the first time that Ubiquilin 1 regulates APP metabolism in the human neuroblastoma cell line, SH-SY5Y.
Pivotal Role of Innate and Adaptive Immunity in Anthracycline Chemotherapy of Established Tumors
Authors: Stephen R. Mattarollo, Sherene Loi, Helene Duret, Yuting Ma, Laurence Zitvogel, Mark J. Smyth
Journal: Cancer Research (2011)

We show, in a series of established experimental breast adenocarcinomas and fibrosarcomas induced by carcinogen de novo in mice, that the therapeutic efficacy of doxorubicin treatment is dependent on CD8 T cells and IFN-γ production. Doxorubicin treatment enhances tumor antigen-specific proliferation of CD8 T cells in tumor-draining lymph nodes and promotes tumor infiltration of activated, IFN-γ-producing CD8 T cells. Optimal doxorubicin treatment outcome also requires both interleukin (IL)-1β and IL-17 cytokines, as blockade of IL-1β/IL-1R or IL-17A/IL-17Rα signaling abrogated the therapeutic effect. IL-23p19 had no observed role. The presence of γδ T cells, but not Jα18(+) natural killer T cells, at the time of doxorubicin treatment was also important. In tumor samples taken from breast cancer patients prior to treatment with anthracycline chemotherapy, a correlation between CD8α, CD8β, and IFN-γ gene expression levels and clinical response was observed, supporting their role in the therapeutic efficacy of anthracyclines in humans. Overall, these data strongly support the pivotal contribution of both innate and adaptive immunity in treatment outcomes of anthracycline chemotherapy.