tbuckley/cabot-search huggingface dataset:
Altered thoracic gas compression contributes to improvement in spirometry with lung volume reduction surgery
Authors: A Sharafkhaneh
Journal: Thorax (2005)

<b>Background:</b> Thoracic gas compression (TGC) exerts a negative effect on forced expiratory flow. Lung resistance, effort during a forced expiratory manoeuvre, and absolute lung volume influence TGC. Lung volume reduction surgery (LVRS) reduces lung resistance and absolute lung volume. LVRS may therefore reduce TGC, and such a reduction might explain in part the improvement in forced expiratory flow with the surgery. A study was conducted to determine the effect of LVRS on TGC and the extent to which reduced TGC contributed to an improvement in forced expiratory volume in 1 second (FEV<sub>1</sub>) following LVRS. <b>Methods:</b> The effect of LVRS on TGC was studied using prospectively collected lung mechanics data from 27 subjects with severe emphysema. Several parameters including FEV<sub>1</sub>, expiratory and inspiratory lung resistance (Rle and Rli), and lung volumes were measured at baseline and 6 months after surgery. Effort during the forced manoeuvre was measured using transpulmonary pressure. A novel method was used to estimate FEV<sub>1</sub> corrected for the effect of TGC. <b>Results:</b> At baseline the FEV<sub>1</sub> corrected for gas compression (NFEV<sub>1</sub>) was significantly higher than FEV<sub>1</sub> (p&lt;0.0001). FEV<sub>1</sub> increased significantly from baseline (p&lt;0.005) while NFEV<sub>1</sub> did not change following surgery (p&gt;0.15). TGC decreased significantly with LVRS (p&lt;0.05). Rle and maximum transpulmonary pressure (TP<sub>peak</sub>) during the forced manoeuvre significantly predicted the reduction in TGC following the surgery (Rle: p&lt;0.01; TP<sub>peak</sub>: p&lt;0.0001; adjusted <i>R</i><sup>2</sup> = 0.68). The improvement in FEV<sub>1</sub> was associated with the reduction in TGC after surgery (p&lt;0.0001, adjusted <i>R</i><sup>2</sup> = 0.58). <b>Conclusions:</b> LVRS decreased TGC by improving expiratory flow limitation. In turn, the reduction in TGC decreased its negative effect on expiratory flow and therefore explained, in part, the improvement in FEV<sub>1</sub> with LVRS in this cohort.
Bridging psychology and game theory yields interdependence theory
Authors: P.A.M. van Lange, M. Gallucci
Journal: Behavioral and Brain Sciences (2003)

This commentary focuses on the parts of psychological game theory dealing with preference, as illustrated by team reasoning, and supports the conclusion that these theoretical notions do not contribute above and beyond existing theory in understanding social interaction. In particular, psychology and games are already bridged by a comprehensive, formal, and inherently psychological theory, interdependence theory (Kelley & Thibaut 1978; Kelley et al. 2003), which has been demonstrated to account for a wide variety of social interaction phenomena.
Cholesterol balance and fecal neutral steroid and bile acid excretion in normal men fed dietary fats of different fatty acid composition
Authors: William E. Connor, Donald T. Witiak, Daniel B. Stone, Mark L. Armstrong
Journal: Journal of Clinical Investigation (1969)

Six normal men were fed formula diets containing either highly saturated fat (cocoa butter, iodine value 32) or polyunsaturated fat (corn oil, iodine value 125). The sterol balance technique was used to compare the changes in serum cholesterol concentration with the excretion of fecal steroids. The method used for the analysis of fecal steroids was chemical, with a final identification and quantification by gas-liquid chromatography. It was confirmed that the chemical method for fecal steroid analysis was accurate and reproducible. The three dietary periods were each 3 wk in length. In sequence, cocoa butter (period I), corn oil, and cocoa butter (period III) were fed at 40% of the total calories. All diets were cholesterol free, contained similar amounts of plant sterols, and were identical in other nutrients. Corn oil had a hypocholesterolemic effect. Mean serum cholesterol concentrations were 222 mg/100 ml (cocoa butter, period I), 177 during corn oil, and 225 after the return to cocoa butter. Individual fecal steroids were determined from stools pooled for 7 days. Both neutral steroids and bile acids were altered significantly by dietary polyunsaturated fat. The change in bile acid excretion was considerably greater than the change in neutral steroids. Corn oil caused a greater fecal excretion of both deoxycholic and lithocholic acids. The total mean excretion (milligrams per day) of fecal steroids was 709 for cocoa butter (period I), 915 for corn oil, and 629 for the second cocoa butter period. The enhanced total fecal steroid excretion by the polyunsaturated fat of corn oil created a negative cholesterol balance vis-à-vis the saturated fat of cocoa butter. The hypocholesterolemic effect of polyunsaturated fat was associated with total fecal sterol excretion twice greater than the amount of cholesterol calculated to leave the plasma. This finding suggested possible loss of cholesterol from the tissues as well.
The ICOS/ICOSL Pathway Is Required for Optimal Antitumor Responses Mediated by Anti–CTLA-4 Therapy
Authors: Tihui Fu, Qiuming He, Padmanee Sharma
Journal: Cancer Research (2011)

The anti-CTL-associated antigen 4 (anti-CTLA-4) antibody ipilimumab is the first agent to show improved survival in a randomized phase III trial that enrolled patients with metastatic melanoma. Studies are ongoing to identify mechanisms that elicit clinical benefit in the setting of anti-CTLA-4 therapy. We previously reported that treated patients had an increase in the frequency of T cells expressing the inducible costimulator (ICOS) molecule, a T-cell-specific molecule that belongs to the CD28/CTLA-4/B7 immunoglobulin superfamily. ICOS and its ligand (ICOSL) have been shown to play diverse roles in T-cell responses such as mediating autoimmunity as well as enhancing the development/activity of regulatory T cells. These seemingly opposing roles have made it difficult to determine whether the ICOS/ICOSL pathway is necessary for antitumor responses. To determine whether the ICOS/ICOSL pathway might play a causal role in the antitumor effects mediated by anti-CTLA-4, we conducted studies in ICOS-sufficient and ICOS-deficient mice bearing B16/BL6 melanoma. We show that ICOS(+) T cells comprised a population of Th1 cytokine producing and tumor antigen-specific effector cells. Furthermore, in the absence of ICOS, antitumor T-cell responses elicited by anti-CTLA-4 are significantly diminished, thereby impairing tumor rejection. Our findings establish that the ICOS/ICOSL pathway is necessary for the optimal therapeutic effect of anti-CTLA-4, thus implicating this pathway as a target for future combinatorial strategies to improve the efficacy of anti-CTLA-4 therapy.
Incidence and clinical importance of perioperative histamine release: randomised study of volume loading and antihistamines after induction of anaesthesia
Authors: W. Lorenz, H. Sitter, D. Weber, M. Rothmund, B. Stinner, D. Duda, W. Dick, H. Menke, Th Junginger, A. Doenicke, Ch Ohmann, A. Black, M.J.R. Healy
Journal: The Lancet (1994)
Sequential Intraperitoneal Topotecan and Oral Etoposide Chemotherapy in Recurrent Platinum-Resistant Ovarian Carcinoma
Authors: Anil K. Sood, Richard Lush, John P. Geisler, Mark S. Shahin, Linda Sanders, Dan Sullivan, Richard E. Buller, Joel I. Sorosky
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose is to investigate the safety and efficacy of i.p. topotecan and oral etoposide as salvage treatment for patients with platinum-resistant ovarian or primary peritoneal cancer. Experimental Design: Patients were treated with i.p. topotecan initial dose, 1 mg/m2 on days 1 to 5, followed by oral etoposide 100 mg on days 6 to 9 of a 28-day cycle for six cycles. Dose reduction of topotecan was used for severe bone marrow suppression. Peritoneal (topotecan) and plasma (topotecan and etoposide) levels were assessed at multiple time points using high-pressure liquid chromatography. Results: Twenty-two patients (mean age, 61 years) with a median of 1.5 prior treatments were enrolled. Etoposide peak plasma concentrations ranged from 1.9 to 6.9 μg/mL (mean, 3.6 μg/mL). Topotecan plasma levels rose with increasing peritoneal concentration and were detectable within 1 hour but tended to decrease rapidly to below detectable levels within 24 hours. The peak plasma concentration of topotecan was 12.82 ± 8.55 μg/mL with a plasma half-life of 6.17 ± 2.75 hours. A total of 104 cycles was administered; 14 patients (64%) completed all six planned cycles. All patients were evaluable for toxicity, and 21 patients were evaluable for response. The most common grade 4 toxicities were neutropenia and thrombocytopenia in eight and four patients (36 and 18%), respectively. There were no treatment-related deaths. The overall response rate was 38% [complete response, three (14%); partial response, five (24%)]. Seven patients had stable disease and six progressed while on treatment. Conclusions: The combination of i.p. topotecan and oral etoposide is an active and well-tolerated regimen in platinum-resistant ovarian carcinoma. Additional studies investigating topotecan in combination with etoposide are warranted.
The Liver May Act as a Firewall Mediating Mutualism Between the Host and Its Gut Commensal Microbiota
Authors: Maria L. Balmer, Emma Slack, Andrea de Gottardi, Melissa A. E. Lawson, Siegfried Hapfelmeier, Luca Miele, Antonio Grieco, Hans Van Vlierberghe, René Fahrner, Nicola Patuto, Christine Bernsmeier, Francesca Ronchi, Madeleine Wyss, Deborah Stroka, Nina Dickgreber, Markus H. Heim, Kathy D. McCoy, Andrew J. Macpherson
Journal: Science Translational Medicine (2014)

The liver forms a firewall that protects against vascular-borne gut microbes and is commonly impaired in liver disease.
Glycemic Effects of Postmenopausal Hormone Therapy: The Heart and Estrogen/progestin Replacement Study: A Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Alka M. Kanaya, David Herrington, Eric Vittinghoff, Feng Lin, Deborah Grady, Vera Bittner, Jane A. Cauley, Elizabeth Barrett-Connor
Journal: Annals of Internal Medicine (2003)

Background: Randomized trials of postmenopausal hormone therapy have found differing effects on fasting glucose levels. No trial has evaluated the effect of hormone therapy on diabetes incidence. Objective: To evaluate the effect of hormone therapy on fasting glucose level and incident diabetes. Design: Randomized, double-blind, placebo-controlled trial. Setting: 20 U.S. clinical centers. Participants: 2763 postmenopausal women with coronary heart disease who were followed for 4.1 years. At baseline, 734 women had diabetes, 218 women had impaired fasting glucose, and 1811 women were normoglycemic; the 2029 women without diabetes were followed for incident diabetes. Intervention: 0.625 mg of conjugated estrogen plus 2.5 mg of medroxyprogesterone acetate daily, or placebo. Measurements: Fasting glucose level was measured at baseline, at year 1, and at the end of the trial. Incident diabetes was defined by self-report of diabetes or disease complication, fasting glucose level of 6.9 mmol/L or greater ( 126 mg/dL), or initiation of therapy with diabetes medication. Results: Fasting glucose levels increased significantly among women assigned to placebo but did not change among women receiving hormone therapy. The incidence of diabetes was 6.2% in the hormone therapy group and 9.5% in the placebo group (relative hazard, 0.65 [95% CI, 0.48 to 0.89]; P = 0.006). The number needed to treat for benefit to prevent one case of diabetes was 30 (CI, 18 to 103). Changes in weight and waist circumference did not mediate this effect. Conclusions: In women with coronary disease, hormone therapy reduced the incidence of diabetes by 35%. This observation provides important insights into the metabolic effects of postmenopausal hormones but is insufficient to recommend the use of hormones for secondary prevention of heart disease.
Reviving the attack against HIV
Authors: Amy Maxmen
Journal: The Journal of Experimental Medicine (2008)

Researchers breathe life into exhausted T cells in a study on page 2763.






Figure 1

HIV-specific T cells that express TIM-3 produce less IFN-γ.




HIV beats the immune system in part because killer T cells stop fighting the virus. PD-1, a T cell inhibitory protein that normally prevents over-inflammation, was recently associated with chronic HIV. Now Jones et al. identify another manipulated manager, TIM-3.

When CD4+ T cells express the glycoprotein TIM-3, proliferation and cytokine production are suppressed. Because disruption of TIM-3 is known to induce hyperactive inflammatory responses, as seen in autoimmune diseases like multiple sclerosis, Jones et al. predicted that the opposite might be true in HIV infection. The team assessed T cells from HIV patients and found that high levels of the protein indeed corresponded to a heavy viral load.

TIM-3–expressing CD4+ and CD8+ T cells from HIV-infected patients secreted far less interferon (IFN)-γ and TNF than did cells without TIM-3. And blocking TIM-3's ligand reversed this effect. Although the effect of blocking TIM-3 and PD-1 is similar, these molecules were found on distinct populations of CD8+ T cells.

Half of the participants undergoing antiretroviral therapy maintained high TIM-3 expression, even after their viral loads diminished, suggesting to the authors that TIM-3 upregulation may be irreversible in some individuals. And obstructing its signals could be an important means of controlling the underlying virus that persists despite therapy.

Many of the steps between the virus and TIM-3 manipulation aren't yet known, and it appears that HIV isn't the only T cell exhauster. Learning how to revive tired cells might therefore help patients with other chronic infections as well. AM
Therapeutic AAV9-mediated Suppression of Mutant SOD1 Slows Disease Progression and Extends Survival in Models of Inherited ALS
Authors: Kevin D Foust, Desirée L Salazar, Shibi Likhite, Laura Ferraiuolo, Dara Ditsworth, Hristelina Ilieva, Kathrin Meyer, Leah Schmelzer, Lyndsey Braun, Don W Cleveland, Brian K Kaspar
Journal: Molecular Therapy (2013)

Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials.
Identification of α-Chloro Fatty Aldehydes and Unsaturated Lysophosphatidylcholine Molecular Species in Human Atherosclerotic Lesions
Authors: Arun K. Thukkani, Jane McHowat, Fong-Fu Hsu, Marie-Luise Brennan, Stanley L. Hazen, David A. Ford
Journal: Circulation (2003)

Background— A role for myeloperoxidase (MPO) as a mediator of coronary artery disease and acute coronary syndromes has recently received considerable attention. Although active MPO and hypochlorite-modified proteins and peptides have been detected in human atherosclerotic lesions, detection of novel chlorinated oxidized lipid species with proatherogenic properties in vivo has not yet been reported. In this study we show that MPO-generated reactive chlorinating species promote selective oxidative cleavage of plasmalogens, liberating α-chloro fatty aldehydes and unsaturated lysophosphatidylcholine in human atherosclerotic lesions. Methods and Results— Stable isotope dilution gas chromatography–mass spectrometry methods were used to identify and quantitate the α-chloro fatty aldehyde, 2-chlorohexadecanal, in atherosclerotic versus normal human aorta. Compared with normal aorta, 2-chlorohexadecanal levels were elevated more than 1400-fold in atherosclerotic tissues. Parallel electrospray ionization mass spectrometry studies confirmed 34- and 20-fold increases in the plasmalogen cooxidation products, unsaturated lysophosphatidylcholine molecular species containing linoleic and arachidonic acid, respectively, within atherosclerotic compared with normal aorta. Unsaturated lysophosphatidylcholine containing docosahexaenoic acid was also detected in atherosclerotic but not in normal aorta. Exposure of primary human coronary artery endothelial cells to plasmalogen-derived lysophosphatidylcholine molecular species produced marked increases in P-selectin surface expression. Conclusions— The present studies demonstrate that plasmalogens are attacked by MPO-derived reactive chlorinating species within human atheroma. The resultant species formed, α-chloro fatty aldehydes and unsaturated lysophospholipids, possess proatherogenic properties, as shown by induction of P-selectin surface expression in primary human coronary artery endothelial cells.
Common variation at 10p12.31 near MLLT10 influences meningioma risk
Authors: Sara E Dobbins, Peter Broderick, Beatrice Melin, Maria Feychting, Christoffer Johansen, Ulrika Andersson, Thomas Brännström, Johannes Schramm, Bianca Olver, Amy Lloyd, Yussanne P Ma, Fay J Hosking, Stefan Lönn, Anders Ahlbom, Roger Henriksson, Minouk J Schoemaker, Sarah J Hepworth, Per Hoffmann, Thomas W Mühleisen, Markus M Nöthen, Susanne Moebus, Lewin Eisele, Michael Kosteljanetz, Kenneth Muir, Anthony Swerdlow, Matthias Simon, Richard S Houlston
Journal: Nature Genetics (2011)
How to read a paper: Papers that report diagnostic or screening tests
Authors: T Greenhalgh
Journal: BMJ (1997)

If you are new to the concept of validating diagnostic tests, the following example may help you. Ten men are awaiting trial for murder. Only three of them actually committed a murder; the seven others are innocent of any crime. A jury hears each case and finds six of the men guilty of murder. Two of the convicted are true murderers. Four men are wrongly imprisoned. One murderer walks free.



PETER BROWN



This information can be expressed in what is known as a two by two table (table 1). Note that the “truth” (whether or not the men really committed a murder) is expressed along the horizontal title row, whereas the jury's verdict (which may or may not reflect the truth) is expressed down the vertical row.

View this table:

Table 1 
Two by two table showing outcome of trial for 10 men accused of murder



These figures, if they are typical, reflect several features of this particular jury:

These five features constitute, respectively, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of this jury's performance. The rest of this article considers these five features applied to diagnostic (or screening) tests when compared with a “true” diagnosis or gold standard. A sixth feature—the likelihood ratio—is introduced at the end of the article.

Our window cleaner told me that he had been feeling thirsty recently and had …
Thymoquinone attenuates tumor growth in ApcMin mice by interference with Wnt-signaling
Authors: Michaela Lang, Melanie Borgmann, Georg Oberhuber, Rayko Evstatiev, Kristine Jimenez, Kyle W Dammann, Manuela Jambrich, Vineeta Khare, Christoph Campregher, Robin Ristl, Christoph Gasche
Journal: Molecular Cancer (2013)

Abstract Background Patients with familial adenomatous polyposis (FAP) are at increased risk for the development of colorectal cancer. Surgery and chemoprevention are the most effective means to prevent cancer development. Thymoquinone (TQ) is considered the main compound of the volatile Nigella sativa seed oil and has been reported to possess anticarcinogenic properties. In this study we evaluated the chemopreventive properties of TQ in a mouse model of FAP. Methods APC Min mice were fed with chow containing 37.5 mg/kg or 375 mg/kg TQ for 12 weeks. H&amp;E stained intestine tissue sections were assessed for tumor number, localization, size, and grade. Immunohistochemistry for β-catenin, c-myc, Ki-67 and TUNEL-staining was performed to investigate TQ’s effect on major colorectal cancer pathways. TQ’s impact on GSK-3β and β-catenin were studied in RKO cells. Results 375 mg/kg but not 37.5 mg/kg TQ decreased the number of large polyps in the small intestine of APC Min mice. TQ induced apoptosis in the neoplastic tissue but not in the normal mucosa. Furthermore, upon TQ treatment, β-catenin was retained at the membrane and c-myc decreased in the nucleus, which was associated with a reduced cell proliferation in the villi. In vitro , TQ activated GSK-3β, which induced membranous localization of β-catenin and reduced nuclear c-myc expression. Conclusions In summary, TQ interferes with polyp progression in Apc Min mice through induction of tumor-cell specific apoptosis and by modulating Wnt signaling through activation of GSK-3β. Nigella sativa oil (or TQ) might be useful as nutritional supplement to complement surgery and chemoprevention in FAP.
Asthma severity and diagnostic assessment in subjects older than 40 years in a 12-months cohort of patients referred to a tertiary asthma clinic
Authors: Celeste Porsbjerg, Asger Sverrild, Vibeke Backer
Journal: European Respiratory Journal (2013)

Background: Late onset asthma seems to be more severe than asthma in younger adults. However, limited evidence is available on how older asthma patients are generally diagnosed and managed in tertiary care.

Aim: To compare disease severity and diagnostic assessment in older versus younger adults with asthma or suspected asthma.

Methods: A retrospective study of all patients consecutively referred for tertiary asthma specialist assessment over 12 months. Data on symptoms, lung function, NO and airway hyperresponsiveness were assessed.

Results: In total, 283 patients were referred for assessment, of whom 157 (56%) were aged  40 years.

A higher percentage of subjects aged > 40 years had experienced an exacerbation (25% vs 13%, p  40years (mean (SD) FEV1 % of predicted: 81.3% (SD:22.4%) vs 94.4% (SD:17.3%).

In spite of the severity of asthma, the level of diagnostic assessment was lower in older subjects: Symptom frequency was assessed in 16% vs 27%, (p= 0.02), reversibility testing was performed in 44% vs 58% (p=0.01), NO measurement in 49% vs 77% (p< 0.001) and bronchial provocation (mannitol and/or metacholine) in 36% vs 60% (p<0.001).

Conclusion: Among adults referred for specialist assessment for asthma, severity of asthma increased with age, but the intensity of diagnostic assessment decreased, indicating a tendency to underdiagnosis of asthma in older adults.