tbuckley/cabot-search huggingface dataset:
Loss of Thioredoxin Reductase 1 Renders Tumors Highly Susceptible to Pharmacologic Glutathione Deprivation
Authors: Pankaj Kumar Mandal, Manuela Schneider, Pirkko Kölle, Peter Kuhlencordt, Heidi Förster, Heike Beck, Georg W. Bornkamm, Marcus Conrad
Journal: Cancer Research (2010)

Tumor cells generate substantial amounts of reactive oxygen species (ROS), engendering the need to maintain high levels of antioxidants such as thioredoxin (Trx)- and glutathione (GSH)-dependent enzymes. Exacerbating oxidative stress by specifically inhibiting these types of ROS-scavenging enzymes has emerged as a promising chemotherapeutic strategy to kill tumor cells. However, potential redundancies among the various antioxidant systems may constrain this simple approach. Trx1 and thioredoxin reductase 1 (Txnrd1) are upregulated in numerous cancers, and Txnrd1 has been reported to be indispensable for tumorigenesis. However, we report here that genetic ablation of Txnrd1 has no apparent effect on tumor cell behavior based on similar proliferative, clonogenic, and tumorigenic potential. This finding reflects widespread redundancies between the Trx- and GSH-dependent systems based on evidence of a bypass to Txnrd1 deficiency by compensatory upregulation of GSH-metabolizing enzymes. Because the survival and growth of Txnrd1-deficient tumors were strictly dependent on a functional GSH system, Txnrd1-/- tumors were highly susceptible to experimental GSH depletion in vitro and in vivo. Thus, our findings establish for the first time that a concomitant inhibition of the two major antioxidant systems is highly effective in killing tumor, highlighting a promising strategy to combat cancer.
STUDIES ON THE ELECTRICAL SYSTOLE (“Q-T” INTERVAL) OF THE HEART
Authors: S. N. Cheer, F. R. Dieuaide
Journal: Journal of Clinical Investigation (1931)

Electrocardiographic measurements of a normal individual, (male), during a 24-hour period Time "~~~~'R-R " "Q0-T"v Time interval interval K It seconds seconds 9:30 a.m.0.925 0.350 0.364 10:30 a.m.0.900 0.358 0.377 11:30 a.m.0
Atopic Disease and Risk of Non–Hodgkin Lymphoma: An InterLymph Pooled Analysis
Authors: Claire M. Vajdic, Michael O. Falster, Silvia de Sanjose, Otoniel Martínez-Maza, Nikolaus Becker, Paige M. Bracci, Mads Melbye, Karin Ekström Smedby, Eric A. Engels, Jennifer Turner, Paolo Vineis, Adele Seniori Costantini, Elizabeth A. Holly, Eleanor Kane, John J. Spinelli, Carlo La Vecchia, Tongzhang Zheng, Brian C-H. Chiu, Luigino Dal Maso, Pierluigi Cocco, Marc Maynadié, Lenka Foretova, Anthony Staines, Paul Brennan, Scott Davis, Richard Severson, James R. Cerhan, Elizabeth C. Breen, Brenda Birmann, Wendy Cozen, Andrew E. Grulich
Journal: Cancer Research (2009)

We performed a pooled analysis of data on atopic disease and risk of non-Hodgkin lymphoma (NHL) from 13 case-control studies, including 13,535 NHL cases and 16,388 controls. Self-reported atopic diseases diagnosed 2 years or more before NHL diagnosis (cases) or interview (controls) were analyzed. Pooled odds ratios (OR) and 95% confidence intervals (95% CI) were computed in two-stage random-effects or joint fixed-effects models, and adjusted for age, sex, and study center. When modeled individually, lifetime history of asthma, hay fever, specific allergy (excluding hay fever, asthma, and eczema), and food allergy were associated with a significant reduction in NHL risk, and there was no association for eczema. When each atopic condition was included in the same model, reduced NHL risk was only associated with a history of allergy (OR, 0.80; 95% CI, 0.68-0.94) and reduced B-cell NHL risk was associated with history of hay fever (OR, 0.85; 95% CI, 0.77-0.95) and allergy (OR, 0.84; 95% CI, 0.76-0.93). Significant reductions in B-cell NHL risk were also observed in individuals who were likely to be truly or highly atopic-those with hay fever, allergy, or asthma and at least one other atopic condition over their lifetime. The inverse associations were consistent for the diffuse large B-cell and follicular subtypes. Eczema was positively associated with lymphomas of the skin; misdiagnosis of lymphoma as eczema is likely, but progression of eczema to cutaneous lymphoma cannot be excluded. This pooled study shows evidence of a modest but consistent reduction in the risk of B-cell NHL associated with atopy.
Lack of Association Between Residual Insulin Production and Glucagon Response to Hypoglycemia in Youth With Short Duration of Type 1 Diabetes
Authors: Jennifer Sherr, Dongyuan Xing, Katrina J. Ruedy, Roy W. Beck, Craig Kollman, Bruce Buckingham, Neil H. White, Larry Fox, Eva Tsalikian, Stuart Weinzimer, Ana Maria Arbelaez, William V. Tamborlane
Journal: Diabetes Care (2013)

To examine the loss of glucagon response to hypoglycemia and its relationship with residual β-cell function early in the course of type 1 diabetes (T1D) in youth.
Asthma aggravation, combustion, and stagnant air
Authors: Gary Norris, Timothy Larson, Jane Q. Koenig, Candis Claiborn, Lianne Sheppard, Dennis Finn
Journal: Thorax (2000)

<h3>BACKGROUND</h3> The relationship between current concentrations of ambient air pollution and adverse health effects is controversial. We report a meteorological index of air stagnation that is associated with daily visits to the emergency department for asthma in two urban areas. <h3>METHODS</h3> Data on daily values of a stagnation persistence index and visits to the emergency department for asthma were collected for approximately two years in Spokane, Washington, USA and for 15 months in Seattle, Washington, USA. The stagnation persistence index represents the number of hours during the 24 hour day when surface wind speeds are less than the annual hourly median value, an index readily available for most urban areas. Associations between the daily stagnation persistence index and daily emergency department visits for asthma were tested using a generalised additive Poisson regression model. A factor analysis of particulate matter (PM<sub>2.5</sub>) composition was performed to identify the pollutants associated with increased asthma visits. <h3>RESULTS</h3> The relative rate of the association between a visit to the emergency department for asthma and the stagnation persistence index was 1. 12 (95% CI 1.05 to 1.19) in Spokane and 1.21 (95% CI 1.09 to 1.35) in Seattle for an increase of 11 and 10 hours, respectively, of low wind speed in a given day. The stagnation persistence index was only correlated with one set of factor loadings; that cluster included the stagnation persistence index, carbon monoxide, and organic/elemental carbon. <h3>CONCLUSION</h3> Increased air stagnation was shown to be a surrogate for accumulation of the products of incomplete combustion, including carbon monoxide and fine particulate levels of organic and elemental carbon, and was more strongly associated with asthma aggravation than any one of the measured pollutants.
Should I send my patient with previous giant cell arteritis for imaging of the thoracic aorta? A systematic literature review and meta-analysis
Authors: Sarah Louise Mackie, Elizabeth M A Hensor, Ann W Morgan, Colin T Pease
Journal: Annals of the Rheumatic Diseases (2012)

To review the literature in order to estimate how many previously unknown thoracic aortic aneurysms (TAAs) and thoracic aortic dilatations (TADs) might be detected by systematic, cross-sectional aortic imaging of patients with giant cell arteritis (GCA).A systematic literature review was performed using Ovid Medline, Embase and the Cochrane Library. Studies potentially relevant to TAA/TAD were evaluated by two authors independently for relevance, bias and heterogeneity. Meta-analysis was performed using a random-effects model to estimate pooled prevalence.Two analyses of routinely collected administrative data suggested a threefold risk of TAA/dissection in GCA compared with controls. In GCA cohorts without systematic imaging, 2-8% had TAA. In the two best-reported studies, aneurysm dissection/rupture occurred in 1% and 6% of GCA cases. Aortic imaging studies had a variety of TAA/TAD definitions, imaging methods and time points. There were limited data on age-matched controls. Three studies suggested that male sex may be a risk factor for TAA/TAD in GCA. On average, five to ten patients with GCA would need aortic imaging to detect one previously unknown TAA/TAD.The data support an association between GCA and TAA/TAD compared with age-matched controls, but the true relative risk, and the time course of that risk, remains unclear. It is also unclear whether chest radiography is a sufficiently sensitive screening tool. Clinicians should retain a high index of suspicion for aortic pathology in patients with GCA. Before ordering imaging, clinicians should consider whether, and how, detecting aortic pathology would affect a patient's management.
Impact of Renin Angiotensin System Modulation on the Hyperfiltration State in Type 1 Diabetes
Authors: Etienne B. Sochett, David Z.I. Cherney, Jacqueline R. Curtis, Maria G. Dekker, James W. Scholey, Judith A. Miller
Journal: Journal of the American Society of Nephrology (2006)

The initial stages of diabetic nephropathy are characterized by glomerular hyperfiltration and hypertension, processes that have been linked to initiation and progression of renal disease. Renin angiotensin system (RAS) blockade is commonly used to modify the hyperfiltration state and delay progression of renal disease. Despite this therapy, many patients progress to ESRD, suggesting heterogeneity in the response to RAS modulation. The role of the RAS in the hyperfiltration state in adolescents with uncomplicated type 1 diabetes was examined, segregated on the basis of the presence of hyperfiltration. Baseline renal hemodynamic function was characterized in 22 patients. Eleven patients exhibited glomerular hyperfiltration (GFR>or=135 ml/min), and in the remaining 11 patients, the GFR was <130 ml/min. Renal hemodynamic function was assessed in response to a graded angiotensin II (AngII) infusion during euglycemic conditions and again after 21 d of angiotensin-converting enzyme (ACE) inhibition with enalapril. AngII infusion under euglycemic conditions resulted in a significant decline in GFR and renal plasma flow in the hyperfiltration group but not in the normofiltration group. After ACE inhibition, GFR fell but did not normalize in the hyperfiltration group; the normofiltration group showed no change. These data show significant differences in renal hemodynamic function between hyperfiltering and normofiltering adolescents with type 1 diabetes at baseline, after AngII infusion and ACE inhibition. The response to ACE inhibition and AngII in hyperfiltering patients suggests that vasodilation may complement RAS activation in causing the hyperfiltration state. The interaction between glomerular vasoconstrictors and vasodilators requires examination in future studies.
Efficiency of in vivo purging with rituximab prior to autologous peripheral blood progenitor cell transplantation in B-cellnon-Hodgkin’s lymphoma: a single institution study
Authors: K. Belhadj, M.-H. Delfau-Larue, T. Elgnaoui, F. Beaujean, J.-L. Beaumont, C. Pautas, I. Gaillard, Y. Kirova, A. Allain, P. Gaulard, J.-P. Farcet, F. Reyes, C. Haioun
Journal: Annals of Oncology (2004)
Prevention of bile acid-induced apoptosis by betaine in rat liver
Authors: Dirk Graf, Anna Kordelia Kurz, Roland Reinehr, Richard Fischer, Gerald Kircheis, Dieter Häussinger
Journal: Hepatology (2002)

Bile acid-induced apoptosis plays an important role in the pathogenesis of cholestatic liver disease, and its prevention is of therapeutic interest. The effects of betaine were studied on taurolithocholate 3-sulfate (TLCS) and glycochenodeoxycholate (GCDC)-induced apoptosis in rat hepatocytes in vitro and in vivo . Hepatocyte apoptosis, caspase activation, and poly (ADP-ribose) polymerase (PARP) cleavage, which are normally observed in response to both bile acids, were largely prevented after preincubation of hepatocytes with betaine. Betaine uptake was required for this protective effect, which was already observed at betaine concentrations of 1 mmol/L. Betaine did not affect the TLCS-induced membrane trafficking of CD95 and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptor 2 to the plasma membrane or the TLCS-induced recruitment of Fas-associated death domain (FADD) and caspase 8 to the CD95 receptor. However, betaine largely prevented cytochrome c release and oxidative stress exerted otherwise by TLCS. Inhibition of caspase 9 strongly blunted TLCS-induced caspase-8 activation. Further betaine did not prevent the TLCS-induced c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (Erk), and p38 mitogen-activated protein kinase (p38 MAPK ) activation or TLCS-induced protein kinase B (PKB) dephosphorylation. The protective betaine effect was insensitive to inhibition of Erks by PD089059, of p38 MAPK by SB203580, or of phosphatidylinositol 3-kinase (PI3-kinase) by LY294002. Betaine supplementation in the drinking water significantly ameliorated in vivo hepatocyte apoptosis following bile duct ligation. In conclusion, this study identifies betaine as a potent protectant against bile acid-induced apoptosis in vivo and in vitro , and its antiapoptotic action largely resides on an inhibition of the proapoptotic mitochondrial pathway.
Emerging Antiviral Strategies to Interfere with Influenza Virus Entry
Authors: Evelien Vanderlinden, Lieve Naesens
Journal: Medicinal Research Reviews (2013)

Influenza A and B viruses are highly contagious respiratory pathogens with a considerable medical and socioeconomical burden and known pandemic potential. Current influenza vaccines require annual updating and provide only partial protection in some risk groups. Due to the global spread of viruses with resistance to the M2 proton channel inhibitor amantadine or the neuraminidase inhibitor oseltamivir, novel antiviral agents with an original mode of action are urgently needed. We here focus on emerging options to interfere with the influenza virus entry process, which consists of the following steps: attachment of the viral hemagglutinin to the sialylated host cell receptors, endocytosis, M2-mediated uncoating, low pH-induced membrane fusion, and, finally, import of the viral ribonucleoprotein into the nucleus. We review the current functional and structural insights in the viral and cellular components of this entry process, and the diverse antiviral strategies that are being explored. This encompasses small molecule inhibitors as well as macromolecules such as therapeutic antibodies. There is optimism that at least some of these innovative concepts to block influenza virus entry will proceed from the proof of concept to a more advanced stage. Special attention is therefore given to the challenging issues of influenza virus (sub)type-dependent activity or potential drug resistance.
Postmenopausal Hormone Therapy and Changes in Mammographic Density
Authors: Fränzel J.B. van Duijnhoven, Petra H.M. Peeters, Ruth M.L. Warren, Sheila A. Bingham, Paulus A.H. van Noord, Evelyn M. Monninkhof, Diederick E. Grobbee, Carla H. van Gils
Journal: Journal of Clinical Oncology (2007)

Hormone therapy (HT) use has been associated with an increased breast cancer risk. We explored the underlying mechanism further by determining the effects of HT on mammographic density, a measure of dense tissue in the breast and a consistent breast cancer risk factor.A total of 620 HT users and 620 never users from the Dutch Prospect-European Prospective Investigation into Cancer and Nutrition (EPIC) cohort and 175 HT users and 161 never users from the United Kingdom EPIC-Norfolk cohort were included. For HT users, one mammogram before and one mammogram during HT use was included. For never users, mammograms with similar time intervals were included. Mammographic density was assessed using a computer-assisted method. Changes in density were analyzed using linear regression.The median time between mammograms was 3.0 years and the median duration of HT use was 1 year. The absolute mean decline in percent density was larger in never users (7.3%) than in estrogen therapy users (6.4%; P = .22) and combined HT users (3.5%; P < .01). The effect of HT appeared to be high in a small number of women, whereas most women were unaffected.Our results suggest that HT use, and especially estrogen and progestin use, slows the changes from dense patterns to more fatty patterns that are normally seen in women with increasing age. Given that it is postulated that lifetime cumulative exposure to high density may be related to breast cancer risk, a delay in density decline in HT users potentially could explain their increased breast cancer risk.
Language and its role in understanding intentional relations: Research tool or mechanism of development?
Authors: Nancy Budwig, Michael Bamberg
Journal: Behavioral and Brain Sciences (1996)

Abstract In our commentary we elaborate on Barresi &amp; Moore's use of language as a tool. In particular, we highlight the importance of cognitive linguistic research with its emphasis on the relation between morpnosyntax and intentional schemes. We also speculate about how language itself might play a role in children's integration of first and third person knowledge.
Authors’ reply to ‘Explaining differential effects of tiotropium on mortality in COPD’
Authors: Christine Jenkins, Richard Beasley
Journal: Thorax (2013)

We thank Dr Lipworth1 for his response to our editorial,2 which we emphasise related to the safety of tiotropium by Respimat, not by Handihaler. We agree that UPLIFT provides very reassuring data regarding the safety of tiotropium administered by the Handihaler device in a chronic obstructive pulmonary disease (COPD) population from which people with significant diseases other than COPD, which could compromise participation or put the patient at risk, were excluded. Patients with a range of commonly encountered comorbidities, including myocardial infarction in the recent 6 months, unstable arrhythmia or hospitalisation for heart failure in the recent 12 months, or need for oxygen therapy >12 h/day, and moderate renal impairment were not eligible for UPLIFT, thereby limiting the generalisability of the findings. We also …
Increased urinary nitrate excretion in rats with adjuvant arthritis.
Authors: D O Stichtenoth, F M Gutzki, D Tsikas, N Selve, S M Bode-Boger, R H Boger, J C Frolich
Journal: Annals of the Rheumatic Diseases (1994)

OBJECTIVES--In rats with adjuvant arthritis measurements were taken of the urinary excretion of nitrate, reflecting endogenous nitric oxide (NO) formation, and cyclic guanosine monophosphate (cGMP). METHODS--Urinary nitrate was determined by gas chromatography, cGMP by radioimmunoassay. RESULTS--A significant (p &lt; 0.001), more than three fold increase of urinary nitrate excretion was found in rats 20 days after induction of adjuvant arthritis compared with non-arthritic rats. There was no significant difference in urinary cGMP excretion between arthritic rats and control animals. CONCLUSION--The data suggest that the dramatic increase of urinary nitrate excretion is due to increase of NO synthesis by the inducible form of NO synthase.
Biological Variation of Homeostasis Model Assessment-Derived Insulin Resistance in Type 2 Diabetes
Authors: Vijay Jayagopal, Eric S. Kilpatrick, Paul E. Jennings, David A. Hepburn, Stephen L. Atkin
Journal: Diabetes Care (2002)

Individuals with type 2 diabetes are particularly vulnerable to cardiovascular disease. Insulin resistance is a major determinant of this increased risk and is a potential therapeutic target. This study was undertaken to establish the natural biological variation of insulin resistance in individuals with type 2 diabetes.The biological variation of insulin resistance was assessed by measuring insulin resistance at 4-day intervals on 10 consecutive occasions in 12 postmenopausal women with diet-controlled type 2 diabetes and in 11 weight- and age-matched postmenopausal women without type 2 diabetes. Insulin resistance was derived using the homeostasis model assessment for insulin resistance (HOMA-IR) method.The distribution of HOMA-IR was log Gaussian in the type 2 diabetic study group and Gaussian in the control group. The HOMA-IR in the type 2 diabetic group was significantly greater than that of the control group (mean +/- SD: 4.33 +/- 2.3 vs. 2.11 +/- 0.79 units, P = 0.001). After accounting for analytical variation, the mean intraindividual variation was also substantially greater in the type 2 diabetic group than in the control group (mean 1.05 vs. 0.15, P = 0.001). Consequently, at any level of HOMA-IR, a subsequent sample must increase by >90% or decrease by >47% to be considered significantly different from the first.HOMA-IR is significantly greater and more variable for individuals with type 2 diabetes. Therefore, this inherent variability needs to be accounted for in studies evaluating therapeutic reduction of HOMA-IR in this group.
Radiographic, scintigraphic, and gas-dilution estimates of individual lung and lobar volumes in man.
Authors: R J Pierce, D J Brown, D M Denison
Journal: Thorax (1980)

We describe a method of separately determining the volumes of the right and left lungs from conventional chest radiographs and of determining the volumes of individual lobes and pathological spaces, whenever their boundaries are visible radiologically or can be displayed scintigraphically--for example, during fibreoptic bronchoscopy. Scintigrams of individual lungs, lobes, and segments are obtained by deflecting a stream of air marked with 81m krypton down the suction channel of the bronchoscope into the appropriate bronchus during inspiration, followed by a breath-hold during which the image is recorded with a gamma camera. Both radiographic and scintigraphic methods have been validated by comparison with argon dilution estimates of individual lung and lobar volumes also obtained at bronchoscopy, and results for the three methods in normal subjects are presented. Used in conjunction with bronchoscopic soluble gas uptake studies, these volume measurements permit precise estimation of effective perfusion, tissue and water volume, and gas transfer at lobar and segmental level. Individual lung and lobar volumes can be used to quantify lung and lobar collapse and compression, mediastinal shift, regional ventilation and gas trapping, and phrenic paresis.