tbuckley/cabot-search huggingface dataset:
Thrombolysis for Pulmonary Embolism and Risk of All-Cause Mortality, Major Bleeding, and Intracranial Hemorrhage
Authors: Saurav Chatterjee, Anasua Chakraborty, Ido Weinberg, Mitul Kadakia, Robert L. Wilensky, Partha Sardar, Dharam J. Kumbhani, Debabrata Mukherjee, Michael R. Jaff, Jay Giri
Journal: JAMA (2014)

IMPORTANCE Thrombolytic therapy may be beneficial in the treatment of some patients with pulmonary embolism.To date, no analysis has had adequate statistical power to determine whether thrombolytic therapy is associated with improved survival, compared with conventional anticoagulation.OBJECTIVE To determine mortality benefits and bleeding risks associated with thrombolytic therapy compared with anticoagulation in acute pulmonary embolism, including the subset of hemodynamically stable patients with right ventricular dysfunction (intermediate-risk pulmonary embolism).
Toxicity of Older and Younger Patients Treated With Adjuvant Chemotherapy for Node-Positive Breast Cancer: The Cancer and Leukemia Group B Experience
Authors: Hyman B. Muss, Donald A. Berry, Constance Cirrincione, Daniel R. Budman, I. Craig Henderson, Marc L. Citron, Larry Norton, Eric P. Winer, Clifford A. Hudis
Journal: Journal of Clinical Oncology (2007)

Older node-positive patients treated with newer adjuvant chemotherapy regimens have improvements in relapse-free and overall survival similar to younger patients. We compared toxicity of older and younger patients in three randomized trials of adjuvant chemotherapy.Toxicity data were available for 93% of 6,642 patients enrolled. The three trials included: Cancer and Leukemia Group B (CALGB) 8541, a comparison of cyclophosphamide, doxorubicin, and fluorouracil in three dose schedules; CALGB 9344: cyclophosphamide and doxorubicin with or without paclitaxel; and CALGB 9741: cyclophosphamide, doxorubicin, and paclitaxel every 2 versus every 3 weeks. National Cancer Institute grade 3 to 5 toxicities were compared among age groups.Seven percent of patients (n = 458) were age 65 or older, 3% were 70 or older, 38% were 51 to 64, and 55% were 50 or younger. Twenty-four deaths (0.4%) were attributed to treatment; seven (1.5%) of 486 in patients 65 or older, 10 (0.40%) of 2,480 in patients who were 51 to 64 years, and seven (0.19%) of 3,676 occurred in patients younger than 50. In multivariate analysis, older patients were significantly more likely to have grade 4 hematologic toxicity, to have discontinued treatment for toxicity, or to have died of acute myeloid leukemia/myelodysplastic syndrome. There were no significant differences in grade 3 to 4 nonhematologic toxicity.Healthy older patients who met the strict eligibility criteria for these trials had a higher rate of hematologic toxicity and treatment-related deaths than younger patients, but no increase in nonhematologic toxicity. Elderly patients treated with newer adjuvant chemotherapy regimens derive the same benefits from newer chemotherapy regimens as younger patients but should be cautioned about the increased risk of toxicity and treatment-related death.
Influence of secular trends and sample size on reference equations for lung function tests
Authors: P.H. Quanjer, J. Stocks, T.J. Cole, G.L. Hall, S. Stanojevic
Journal: European Respiratory Journal (2010)

The aim of our study was to determine the contribution of secular trends and sample size to lung function reference equations, and establish the number of local subjects required to validate published reference values. 30 spirometry datasets collected between 1978 and 2009 provided data on healthy, white subjects: 19,291 males and 23,741 females aged 2.5–95 yrs. The best fit for forced expiratory volume in 1 s (FEV 1) , forced vital capacity (FVC) and FEV 1 /FVC as functions of age, height and sex were derived from the entire dataset using GAMLSS. Mean z-scores were calculated for individual datasets to determine inter-centre differences. This was repeated by subdividing one large dataset (3,683 males and 4,759 females) into 36 smaller subsets (comprising 18–227 individuals) to preclude differences due to population/technique. No secular trends were observed and differences between datasets comprising &gt;1,000 subjects were small (maximum difference in FEV 1 and FVC from overall mean: 0.30– -0.22 z-scores). Subdividing one large dataset into smaller subsets reproduced the above sample size-related differences and revealed that at least 150 males and 150 females would be necessary to validate reference values to avoid spurious differences due to sampling error. Use of local controls to validate reference equations will rarely be practical due to the numbers required. Reference equations derived from large or collated datasets are recommended.
Lung cancer in lifelong non-smokers. Edinburgh Lung Cancer Group.
Authors: S Capewell, R Sankaran, D Lamb, M McIntyre, M F Sudlow
Journal: Thorax (1991)

<b>Objectives</b> To explore trends in suicide in young people to investigate the recent observation that after year on year rises in the 1970s, 1980s, and early 1990s, rates in young men are now declining. <b>Design</b> Time trend analysis. <b>Setting</b> England and Wales, 1968-2005. <b>Population</b> Men and women aged 15-34 years. <b>Results</b> Since the 1990s, rates of suicide in young men have declined steadily and by 2005 they were at their lowest level for almost 30 years. This decline is partly because of a reduction in poisoning with car exhaust gas as an increased number of cars have catalytic converters; but there have been declines in suicides from all common methods, including hanging, suggesting a more pervasive effect. Other risk factors for suicide, such as unemployment and divorce, have also decreased. Possible recent reductions in alcohol use among young men and increases in prescribing of antidepressants do not seem to be temporally related to the decline in suicide. <b>Conclusions</b> Suicide rates in young men have declined markedly in the past 10 years in England and Wales. Reductions in key risk factors for suicide, such as unemployment, might be contributing to lower rates.
Activating Mutations of the Noonan Syndrome-Associated <b> <i>SHP2/PTPN11</i> </b> Gene in Human Solid Tumors and Adult Acute Myelogenous Leukemia
Authors: Mohamed Bentires-Alj, J. Guillermo Paez, Frank S. David, Heike Keilhack, Balazs Halmos, Katsuhiko Naoki, John M. Maris, Andrea Richardson, Alberto Bardelli, David J. Sugarbaker, William G. Richards, Jinyan Du, Luc Girard, John D. Minna, Mignon L. Loh, David E. Fisher, Victor E. Velculescu, Bert Vogelstein, Matthew Meyerson, William R. Sellers, Benjamin G. Neel
Journal: Cancer Research (2004)

Abstract The SH2 domain-containing protein-tyrosine phosphatase PTPN11 (Shp2) is required for normal development and is an essential component of signaling pathways initiated by growth factors, cytokines, and extracellular matrix. In many of these pathways, Shp2 acts upstream of Ras. About 50% of patients with Noonan syndrome have germ-line PTPN11 gain of function mutations. Associations between Noonan syndrome and an increased risk of some malignancies, notably leukemia and neuroblastoma, have been reported, and recent data indicate that somatic PTPN11 mutations occur in children with sporadic juvenile myelomonocytic leukemia, myelodysplasic syndrome, B-cell acute lymphoblastic leukemia, and acute myelogenous leukemia (AML). Juvenile myelomonocytic leukemia patients without PTPN11 mutations have either homozygotic NF-1 deletion or activating RAS mutations. Given the role of Shp2 in Ras activation and the frequent mutation of RAS in human tumors, these data raise the possibility that PTPN11 mutations play a broader role in cancer. We asked whether PTPN11 mutations occur in other malignancies in which activating RAS mutations occur at low but significant frequency. Sequencing of PTPN11 from 13 different human neoplasms including breast, lung, gastric, and neuroblastoma tumors and adult AML and acute lymphoblastic leukemia revealed 11 missense mutations. Five are known mutations predicted to result in an activated form of Shp2, whereas six are new mutations. Biochemical analysis confirmed that several of the new mutations result in increased Shp2 activity. Our data demonstrate that mutations in PTPN11 occur at low frequency in several human cancers, especially neuroblastoma and AML, and suggest that Shp2 may be a novel target for antineoplastic therapy.
Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis
Authors: D.L. Shawcross, Y. Sharifi, J.B. Canavan, A.D. Yeoman, R.D. Abeles, N.J. Taylor, G. Auzinger, W. Bernal, J.A. Wendon
Journal: Journal of Hepatology (2010)
Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome
Authors: Duarte C. Barral, José S. Ramalho, Ross Anders, Alistair N. Hume, Holly J. Knapton, Tanya Tolmachova, Lucy M. Collinson, David Goulding, Kalwant S. Authi, Miguel C. Seabra
Journal: Journal of Clinical Investigation (2002)

Griscelli syndrome (GS) patients and the corresponding mouse model ashen exhibit defects mainly in two types of lysosome-related organelles, melanosomes in melanocytes and lytic granules in CTLs. This disease is caused by loss-of-function mutations in RAB27A, which encodes 1 of the 60 known Rab GTPases, critical regulators of vesicular transport. Here we present evidence that Rab27a function can be compensated by a closely related protein, Rab27b. Rab27b is expressed in platelets and other tissues but not in melanocytes or CTLs. Morphological and functional tests in platelets derived from ashen mice are all within normal limits. Both Rab27a and Rab27b are found associated with the limiting membrane of platelet-dense granules and to a lesser degree with α-granules. Ubiquitous transgenic expression of Rab27a or Rab27b rescues ashen coat color, and melanocytes derived from transgenic mice exhibit widespread peripheral distribution of melanosomes instead of the perinuclear clumping observed in ashen melanocytes. Finally, transient expression in ashen melanocytes of Rab27a or Rab27b, but not other Rab's, restores peripheral distribution of melanosomes. Our data suggest that Rab27b is functionally redundant with Rab27a and that the pathogenesis of GS is determined by the relative expression of Rab27a and Rab27b in specialized cell types.
Suppression of in vitro antibody response by a serum factor (SAA) in experimentally induced amyloidosis.
Authors: M D Benson, M A Aldo-Benson, T Shirahama, Y Borel, A S Cohen
Journal: The Journal of Experimental Medicine (1975)

Serum from CBA/J mice made amyloidotic by chronic casein injections has been shown to suppress in vitro antibody response to SRBC. Similar suppression was also found with normal mouse serum but to a much lesser degree. This suppressive activity of both amyloidotic serum and normal serum was removed by absorption of the sera with antiserum to protein AA, the major constituent of casein-induced (secondary) amyloid fibrils. This antiserum to the amyloid fibril protein AA (mol wt 8,400 daltons) detects an immunologically cross-reacting serum alpha globulin (SAA) (mol wt approx. 100,000). It is postulated that the serum factor (SAA) is a regulator of antibody response and may be present in elevated amounts as the result of chronic antigenic stimulation.
Derivation and Validation of Diagnostic Thresholds for Central Blood Pressure Measurements Based on Long-Term Cardiovascular Risks
Authors: Hao-Min Cheng, Shao-Yuan Chuang, Shih-Hsien Sung, Wen-Chung Yu, Alan Pearson, Edward G. Lakatta, Wen-Harn Pan, Chen-Huan Chen
Journal: Journal of the American College of Cardiology (2013)
Do patients with psoriatic arthritis who present early fare better than those presenting later in the disease?
Authors: D. D. Gladman, A. Thavaneswaran, V. Chandran, R. J. Cook
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Background</h3> This investigation aimed to determine whether patients presenting to a psoriatic arthritis (PsA) clinic early in the course of the disease had less severe disease at presentation, and whether disease duration at presentation predicts progression of joint damage. <h3>Methods</h3> Patients followed prospectively in a specialised clinic were divided into those first seen within 2 years of diagnosis (group 1) and those seen with more than 2 years of disease (group 2). The groups were compared with regard to demographics and disease characteristics at presentation. A multivariate analysis using a negative binomial model was conducted to determine whether patients with early disease had less progression of joint damage. <h3>Results</h3> 436 patients were identified in group 1 and 641 patients in group 2. Patients in group 2 were older, had longer duration of psoriasis and PsA, more joint damage and were less likely to be treated with disease-modifying antirheumatic drugs, but had similar level of education and degree of psoriasis severity. After adjusting for age, sex, education level, clinical joint damage at first visit and treatment, group 2 had significantly greater rate of clinical damage progression compared with group 1. <h3>Conclusions</h3> Disease progression is more marked in patients presenting with established disease of more than 2 years9 duration. These results suggest that patients with PsA should be treated earlier in the course of their disease.
Tissue Kallikrein Is Essential for Invasive Capacity of Circulating Proangiogenic Cells
Authors: Gaia Spinetti, Orazio Fortunato, Daniela Cordella, Paola Portararo, Nicolle Kränkel, Rajesh Katare, Graciela B. Sala-Newby, Christine Richer, Marie-Pascale Vincent, Francois Alhenc-Gelas, Giancarlo Tonolo, Sara Cherchi, Costanza Emanueli, Paolo Madeddu
Journal: Circulation Research (2010)

Rationale: Homing of proangiogenic cells (PACs) is guided by chemoattractants and requires proteases to disrupt the extracellular matrix. The possibility that PAC recruitment involves an interaction between proteases and chemotactic factor receptors remains largely unexplored. Objective: To determine the role of human tissue kallikrein (hK1) in PAC invasion and its dependency on kinin receptor signaling. Methods and Results: Human mononuclear cells (MNCs) and culture-selected PACs express and release mature hK1 protein. HK1 gene ( KLK1 ) silencing reduced PACs migratory, invasive, and proangiogenic activities. KLK1 -knockout mouse bone marrow–derived MNCs showed similar impairments and were unable to support reparative angiogenesis in a mouse model of peripheral ischemia. Conversely, adenovirus-mediated KLK1 ( Ad.KLK1 ) gene transfer enhanced PAC-associated functions, whereas the catalytically inactive variant R53H-KLK1 was ineffective. HK1-induced effects are mediated by a kinin B 2 receptor (B 2 R)-dependent mechanism involving inducible nitric oxide synthase and metalloproteinase-2 (MMP2). Lower hK1 protein levels were observed in PACs from type 2 diabetic (T2D) patients, whereas KLK1 mRNA levels were similar to those of healthy subjects, suggesting a post-transcriptional defect. Furthermore, B 2 R is normally expressed on T2D-PACs but remains uncoupled from downstream signaling. Importantly, whereas Ad.KLK1 alone could not restore T2D-PAC invasion capacity, combined KLK1 and B 2 R expression rescued the diabetic phenotype. Conclusions: This study reveals new interactive components of the PACs invasive machinery, acting via protease- and kinin receptor–dependent mechanisms.
Lung deposition from the Turbuhaler in children with cystic fibrosis
Authors: SG Devadason, ML Everard, C MacEarlan, C Roller, QA Summers, P Swift, L Borgstrom, PN Le Souef
Journal: European Respiratory Journal (1997)

Drug delivery to patients using dry powder inhalers, such as the Turbuhaler, is believed to be influenced by the inspiratory flow used. Clinical studies have indicated that this delivery system can be used effectively by children. However, it is not known how the total and weight-corrected dose delivered to the airways varies with age. A deposition study using technetium-99m (99mTc)-labelled budesonide was performed in order to determine the effect of age on delivery. Twenty one children with cystic fibrosis, aged 4-16 yrs, were recruited. They were clinically stable with normal lung function. Initially, a gamma camera scan was taken in front of a flood source containing 37 MBq of 99mTc. Subsequently, subjects inhaled through a low resistance inspiratory filter connected to a commercially available Turbuhaler. Immediately afterwards they inhaled from a noncommercial Turbuhaler containing budesonide labelled with 99mTc, and then underwent anterior and posterior gamma camera scans. Both Turbuhaler inhalers were attached to a portable spirometer and the peak inspiratory flow through the Turbuhaler was recorded for each inhalation. The total body dose was calculated from the dose deposited on the inspiratory filter connected to the commercial Turbuhaler. Analysis of the gamma camera images provided information on the proportion of the radiolabel delivered to the lungs compared to that deposited in the upper airway and stomach. As expected, a highly significant positive correlation was noted between the peak inspiratory flow generated by the patient through the Turbuhaler and the dose delivered to the lung. Similarly, there was a highly significant positive correlation between age and "total lung dose". However, when total lung dose was corrected for body weight, there was a nonsignificant negative correlation with age. This study suggests that the "weight-corrected lung dose" achieved when children aged &gt; 6 yrs use the Turbuhaler, is largely independent of age. It would appear that the flow-dependent properties of this device are such that the reduced peak inspiratory flow generated by younger children results in a lower dose to the lungs, but that this is off-set by their lower body weight. This is unlikely to be a property of other devices with different flow/drug delivery characteristics.
Vascular responses to prostaglandin F 2 alpha in isolated cat lungs.
Authors: A J Lonigro, C A Dawson
Journal: Circulation Research (1975)

Changes in perfusion pressure in response to graded doses of prostaglandin F 2 alpha (PGF 2 alpha) were measured during both forward and retrograde perfusion of isolated cat lungs perfused at a constant flow rate. During forward perfusion, PGF 2 alpha produced a dose-dependent increase in pulmonary artery pressure and a decrease in lung fluid volume. During retrograde perfusion, PGF 2 alpha also produced a dose-dependent increase in perfusion pressure; however, the dose required was fivefold greater than that needed to produce an identical change in pressure during forward perfusion. In addition, during retrograde perfusion, the lung fluid volume increased in response to PGF 2 alpha. These results suggest that the major site of activity of PGF 2 alpha is on the arterial side of the pulmonary vascular bed and that inactivation of PGF 2 alpha by the lung occurs primarily distal to this arterial site of vasomotion. The changes in perfusion pressure in response to PGF 2 alpha were markedly dependent on pH and oxygen tension (Po-2), being abolished by severe alkalosis and potentiated by both acidosis and hypoxia. In contrast, neither serotonin nor norepinephrine exhibited such a pH or Po-2 dependency. Since the ratio of the forward response to the retrograde response was not decreased by alterations of pH or Po-2, their influence on the responses appears to be through interaction at the site of vascular activity rather than through alteration of the rate of prostaglandin inactivation.
Antiretroviral Treatment Regimens and Immune Parameters in the Prevention of Systemic AIDS-Related Non-Hodgkin's Lymphoma
Authors: Justin Stebbing, Brian Gazzard, Sundhiya Mandalia, Alastair Teague, Ashita Waterston, Vanessa Marvin, Mark Nelson, Mark Bower
Journal: Journal of Clinical Oncology (2004)

Purpose Immunosuppression induced by HIV-1 increases the risk of developing non-Hodgkin's lymphoma (NHL). We measured the influence of immunologic factors and highly active antiretroviral therapy (HAART) on this risk. As there are no data demonstrating that specific antiretroviral regimens are effective at protecting from NHL, we compared different HAART regimens. Patients and Methods The protective effect of HAART regimens, containing protease inhibitors (PI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTIs) on the development of NHL was examined in a prospectively recorded cohort of 9,621 HIV-infected individuals. Lymphocyte and natural killer subset data were also entered in univariate and multivariate analyses to establish and stratify the risk of NHL. Results From this cohort of 9,621 patients, 102 have been diagnosed with systemic AIDS-related NHL since 1996, when HAART became freely available here. By univariate analysis, increased age, higher nadir CD4 and CD8 T-cell counts, CD19 B-cell count, CD16/56 natural killer count and exposure to NNRTI or PI containing HAART conferred significant protection against NHL (P &lt; .05). In a multivariate analysis, age, nadir CD4 and CD8 T-cell counts, and exposure to HAART were independent predictors of risk of NHL (P &lt; .02). NNRTI-based HAART (adjusted rate ratio, 0.4; 95% CI, 0.3 to 0.5) was as protective as PI-based HAART, and these were significantly more protective than nucleoside analogues alone (rate ratio, 0.5; 95% CI, 0.4 to 0.7) or no antiretrovirals (P &lt; .001). Conclusion Effective HAART-induced maintenance of CD4 and CD8 counts protects from systemic AIDS-related NHL.
Metabolic Mechanisms in Heart Failure
Authors: Houman Ashrafian, Michael P. Frenneaux, Lionel H. Opie
Journal: Circulation (2007)

Although neurohumoral antagonism has successfully reduced heart failure morbidity and mortality, the residual disability and death rate remains unacceptably high. Though abnormalities of myocardial metabolism are associated with heart failure, recent data suggest that heart failure may itself promote metabolic changes such as insulin resistance, in part through neurohumoral activation. A detrimental self-perpetuating cycle (heart failure --> altered metabolism --> heart failure) that promotes the progression of heart failure may thus be postulated. Accordingly, we review the cellular mechanisms and pathophysiology of altered metabolism and insulin resistance in heart failure. It is hypothesized that the ensuing detrimental myocardial energetic perturbations result from neurohumoral activation, increased adverse free fatty acid metabolism, decreased protective glucose metabolism, and in some cases insulin resistance. The result is depletion of myocardial ATP, phosphocreatine, and creatine kinase with decreased efficiency of mechanical work. On the basis of the mechanisms outlined, appropriate therapies to mitigate aberrant metabolism include intense neurohumoral antagonism, limitation of diuretics, correction of hypokalemia, exercise, and diet. We also discuss more novel mechanistic-based therapies to ameliorate metabolism and insulin resistance in heart failure. For example, metabolic modulators may optimize myocardial substrate utilization to improve cardiac function and exercise performance beyond standard care. The ultimate success of metabolic-based therapy will be manifest by its capacity further to lessen the residual mortality in heart failure.