tbuckley/cabot-search huggingface dataset:
Defective IL-10 expression and in vitro steroid-induced IL-17A in paediatric severe therapy-resistant asthma
Authors: Atul Gupta, Sarah Dimeloe, David F Richards, Emma S Chambers, Cheryl Black, Zoe Urry, Kimuli Ryanna, Emmanuel Xystrakis, Andrew Bush, Sejal Saglani, Catherine M Hawrylowicz
Journal: Thorax (2013)

<h3>Background</h3> Understanding of immune mechanisms underpinning asthma has emerged from studies in adults. It is increasingly recognised, both immunologically and in the development of novel therapies, that adult responses cannot be used accurately to predict those of children. <h3>Methods</h3> Using a well-defined paediatric cohort of severe therapy-resistant asthma (STRA) patients, we investigated cytokine profiles in the airway by analysis of bronchoalveolar lavage fluid. The in vitro capacity of peripheral blood mononuclear cells (PBMCs) for cytokine production was also assessed following polyclonal T cell activation in culture, in the absence or presence of dexamethasone and 1α,25-dihydroxyvitamin D3. <h3>Results</h3> Children with both moderate and STRA had significantly diminished levels of anti-inflammatory interleukin (IL)-10 in airway lavage samples when compared with non-asthmatic controls (p&lt;0.001). Their PBMCs also demonstrated significantly impaired capacity to secrete IL-10 in culture (p&lt;0.001). Dexamethasone regulated the balance between PBMC IL-10 and IL-13 production, increasing IL-10 secretion (p&lt;0.001) and decreasing IL-13 (p&lt;0.001) but unexpectedly enhanced IL-17A production in all groups—most strikingly in the STRA cohort (p&lt;0.001). The inclusion of the active form of vitamin D, 1α,25-dihydroxyvitamin D3, in culture enhanced dexamethasone-induced IL-10 (p&lt;0.05) without marked effects on IL-13 or IL-17A production. Furthermore, systemic vitamin D status directly correlated with airway IL-10 (r=0.6, p&lt;0.01). <h3>Conclusions</h3> These findings demonstrate reduced peripheral and local IL-10 synthesis in paediatric asthma, and support therapeutic augmentation of low circulating vitamin D in severe, difficult-to-treat asthma, in order to correct impaired IL-10 levels. Conversely, steroids enhanced IL-17A levels, and therefore any steroid-sparing properties of vitamin D may have additional benefit in STRA.
Fluticasone/salmeterol is associated with a higher risk of pneumonia and pneumonia related events in comparison with budesonide/formoterol in patients with COPD
Authors: Avais Jabbar
Journal: Thorax (2013)

Combination treatment with inhaled corticosteroids and long acting β2 agonists decrease exacerbations and improve quality of life in patients with chronic obstructive pulmonary disease (COPD) however; a potential concern is an increased risk of pneumonia. Although previous studies have shown the risk of pneumonia to increase with fluticasone/salmeterol versus placebo and tiotropium, there has been no direct comparison of fixed combinations of inhaled corticosteroid/long acting β2 …
Language and conceptual development: Words as essence placeholders
Authors: Fei Xu
Journal: Behavioral and Brain Sciences (2002)

Perhaps in addition to language being a potential medium of domain-general thought, as suggested by Carruthers, language may also play another role in conceptual development: Words are “essence placeholders.” Evidence is presented from studies on categorization, object individuation, and inductive inference in infancy. The assumption that words are essence placeholders may be a mechanism by which infants acquire kind concepts.
Abstract 5315: Human tumor antigen-specific helper and regulatory T cells share common epitope specificity but exhibit distinct T cell repertoire
Authors: Julien Fourcade, Zhaojun Sun, Pavol Kudela, Bratislav Janjic, John M. Kirkwood, Talal El-Hafnawy, Hassane Zarour
Journal: Cancer Research (2010)

Abstract CD4+ regulatory T cells (Tregs) accumulate at tumor sites and play a critical role in the suppression of immune responses against tumor cells. Here, we show that two immunodominant epitopes derived from the tumor antigens (TA) NY-ESO-1 and TRAG-3 stimulate both CD4+ T-helper cells and Tregs. TA-specific Tregs inhibit the proliferation of allogenic T cells, act in a cell-to-cell contact dependent fashion and require antigen activation to suppress IL-2 secretion by T cells. TRAG-3 and NY-ESO-1-specific Tregs exhibit either a Th1-, a Th2- or a Th0-type cytokine profile and dot not produce IL-10 or TGF-β. The Foxp3 levels vary from one Treg clone to another and are significantly lower than those of CD4+CD25high Tregs. In contrast to NY-ESO-1-specific T helper cells, the NY-ESO-1-specific Treg clonotype shares a common TCR CDR3 Vβ usage with Foxp3+CD4+CD25high and CD4+CD25− T cells and was not detectable in PBLs of other NY-ESO-1+ melanoma patients and of healthy donors, suggesting that its recruitment occurs through the peripheral conversion of CD4+CD25− T cells upon chronic antigen exposure. Collectively, our findings demonstrate that the same epitopes spontaneously stimulate both T-helper cells and Tregs in patients with advanced melanoma. They also suggest that TA-specific Treg expansion may be better impaired by therapies aimed at depleting CD4+CD25high Tregs and preventing the peripheral conversion of CD4+CD25− T cells. This work was supported by NIH/NCI Grants CA90360 and CA112198 (HMZ) and Cancer Research Institute grant (HMZ). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5315.
Functional characterization of three intercalated cell subtypes in the rabbit outer cortical collecting duct.
Authors: C Emmons, I Kurtz
Journal: Journal of Clinical Investigation (1994)

The distribution of Na(+)-independent Cl(-)-HCO3- exchange was studied in individual intercalated cells from in vitro perfused rabbit outer CCDs using dual excitation laser scanning confocal microscopy by measuring the pHi response to sequential removal of Cl- from both sides of the tubule. Three patterns of intracellular pH (pHi) response were observed. 39% of intercalated cells had only apical Cl(-)-HCO3- exchange (beta cell), 4% had only basolateral Cl(-)-HCO3- exchange (alpha cell), and 57% had both apical and basolateral Cl(-)-HCO3- exchange (gamma cell). Valinomycin-high K+ voltage clamping had no effect on the pHi response of intercalated cells with bilateral Cl(-)-HCO3- exchange. Although the mean rates of dpHi/dt following apical Cl- removal were similar in beta cells compared to gamma cells, a wide range of apical rates was seen among individual beta and gamma intercalated cells. Neither the apical nor the basolateral Cl(-)-HCO3- exchanger in gamma cells was inhibited by 0.5 mM H2DIDS. Binding of apical peanut lectin was seen both in beta cells and in gamma cells. In 41% of CCDs with four to seven intercalated cells studied, all intercalated cells were of the same subtype. We conclude that the majority of intercalated cells from the rabbit outer CCD have both apical and basolateral Na(+)-independent Cl(-)-HCO3- exchangers (gamma cells), which are stilbene-insensitive. Intercalated cells with only basolateral Cl(-)-HCO3- exchange are very uncommon in the rabbit outer CCD. There is a tendency for all intercalated cells in a given rabbit outer CCD to be of the same subtype (either all beta cells or all gamma cells), suggesting the presence of CCD intertubule heterogeneity at the same cortical level. This finding may account for intertubule differences in transepithelial H(+)-base transport.
Alteration of collagen phenotypes in ischemic cardiomyopathy.
Authors: D Mukherjee, S Sen
Journal: Journal of Clinical Investigation (1991)

Ischemic cardiomyopathy refers to a significant impairment of left ventricular function, a condition resulting from atherosclerotic coronary artery disease. The left ventricular ejection fraction is usually 35% or less, and electron microscopy shows an increased deposition of collagen in the space between the capillaries and the myocytes. The present study shows the alteration in collagen concentration and phenotypes in ischemic cardiomyopathy, and the effect captopril treatment has on these parameters. In patients with ischemic cardiomyopathy, collagen concentration estimated from hydroxyproline increased from 7.96 +/- 1.24 mg/g to 13.9 +/- 1.30 mg/g, P less than 0.05. Ischemic cardiomyopathic patients given captopril therapy had a significantly lower collagen concentration of 10.03 +/- 1.46 mg/g, P less than 0.05. The collagen type I:III ratio decreased from 1.93 +/- 0.52 to 1.23 +/- 0.27 in patients with ischemic cardiomyopathy. Of these patients, those receiving captopril had a collagen type I:III ratio of 1.49 +/- 0.38, which did not differ significantly from the ratio of individuals with normal myocardium. There was no significant difference in type I collagen concentration in the myocardium of normal individuals, patients with ischemic cardiomyopathy, and patients with ischemic cardiomyopathy receiving captopril therapy. The type III collagen concentration increased significantly from 2.56 +/- 0.21 mg/g in normal myocardium to 6.10 +/- 0.58 mg/g in ischemic cardiomyopathic myocardium. Patients receiving captopril had a myocardial collagen type III concentration of 4.87 +/- 0.64 mg/g, which was significantly lower than that found in patients with ischemic cardiomyopathy. An increased deposition of type III collagen may be partly responsible for altering the compliance of the myocardium, resulting in dilatation of the heart and possibly leading to eventual heart failure.
A multicentre randomised phase II study of carboplatin in combination with gemcitabine at standard rate or fixed dose rate infusion in patients with advanced stage non-small-cell lung cancer
Authors: R.A. Soo, L.Z. Wang, L.S. Tham, W.P. Yong, M. Boyer, H.L. Lim, H.S. Lee, M. Millward, S. Liang, P. Beale, S.C. Lee, B.C. Goh
Journal: Annals of Oncology (2006)
Obama's budget changes sex education funding from abstinence-only to comprehensive education
Authors: J. Hopkins Tanne
Journal: BMJ (2009)

Barack Obama’s proposed budget will end most funding for abstinence-only sex education, which will reverse former president George W Bush’s policy. Instead it increases funds for comprehensive sex education.

The proposed budget was sent to Congress on 7 May. Both houses of Congress will consider the budget, pass legislation to appropriate and authorise funds, and reconcile differences between the House of Representatives and Senate versions of the legislation. The 2010 budget year begins on 1 October 2009.

The White House’s budget summary says, “The Budget supports State, community-based, and faith-based efforts to reduce teen pregnancy using …
Risk Adjustment and the Assessment of Disparities in Dialysis Mortality Outcomes
Authors: John Kalbfleisch, Robert Wolfe, Sarah Bell, Rena Sun, Joseph Messana, Tempie Shearon, Valarie Ashby, Robin Padilla, Min Zhang, Marc Turenne, Jeffrey Pearson, Claudia Dahlerus, Yi Li
Journal: Journal of the American Society of Nephrology (2015)

Standardized mortality ratios (SMRs) reported by Medicare compare mortality at individual dialysis facilities with the national average, and are currently adjusted for race. However, whether the adjustment for race obscures or clarifies disparities in quality of care for minority groups is unknown. Cox model-based SMRs were computed with and without adjustment for patient race for 5920 facilities in the United States during 2010. The study population included virtually all patients treated with dialysis during this period. Without race adjustment, facilities with higher proportions of black patients had better survival outcomes; facilities with the highest percentage of black patients (top 10%) had overall mortality rates approximately 7% lower than expected. After adjusting for within-facility racial differences, facilities with higher proportions of black patients had poorer survival outcomes among black and non-black patients; facilities with the highest percentage of black patients (top 10%) had mortality rates approximately 6% worse than expected. In conclusion, accounting for within-facility racial differences in the computation of SMR helps to clarify disparities in quality of health care among patients with ESRD. The adjustment that accommodates within-facility comparisons is key, because it could also clarify relationships between patient characteristics and health care provider outcomes in other settings.
ΔNp63α Repression of the <i>Notch1</i> Gene Supports the Proliferative Capacity of Normal Human Keratinocytes and Cervical Cancer Cells
Authors: Takashi Yugawa, Mako Narisawa-Saito, Yuki Yoshimatsu, Kei Haga, Shin-ichi Ohno, Nagayasu Egawa, Masatoshi Fujita, Tohru Kiyono
Journal: Cancer Research (2010)

The p53 family member p63 is a master regulator of epithelial development. One of its isoforms, DeltaNp63alpha, is predominantly expressed in the basal cells of stratified epithelia and plays a fundamental role in control of regenerative potential and epithelial integrity. In contrast to p53, p63 is rarely mutated in human cancers, but it is frequently overexpressed in squamous cell carcinomas (SCC). However, its functional relevance to tumorigenesis remains largely unclear. We previously identified the Notch1 gene as a novel transcriptional target of p53. Here, we show that DeltaNp63alpha functions as a transcriptional repressor of the Notch1 gene through the p53-responsive element. Knockdown of p63 caused upregulation of Notch1 expression and marked reduction in proliferation and clonogenicity of both normal human keratinocytes and cervical cancer cell lines overexpressing DeltaNp63alpha. Concomitant silencing of Notch1 significantly rescued this phenotype, indicating the growth defect induced by p63 deficiency to be, at least in part, attributable to Notch1 function. Conversely, overexpression of DeltaNp63alpha decreased basal levels of Notch1, increased proliferative potential of normal human keratinocytes, and inhibited both p53-dependent and p53-independent induction of Notch1 and differentiation markers upon genotoxic stress and serum exposure, respectively. These results suggest that DeltaNp63alpha maintains the self-renewing capacity of normal human keratinocytes and cervical cancer cells partly through transcriptional repression of the Notch1 gene and imply a novel pathogenetical significance of frequently observed overexpression of DeltaNp63alpha together with p53 inactivation in SCCs.
Impaired Postprandial Metabolism of Apolipoprotein B48–Containing Remnant Particles in Normolipidemic Subjects With Brittle Type 1 Diabetes
Authors: Jenny W. Su, Jennifer E. Lambert, Michael T. Clandinin, Spencer D. Proctor
Journal: Diabetes Care (2009)

Impaired metabolism of intestinally derived chylomicron remnants has been implicated in the development of atherosclerosis among normolipidemic patients with coronary heart disease (1,2) and, indeed, in other conditions associated with increased vascular disease such as obesity, metabolic syndrome, type 2 diabetes, and familial hypercholesterolemia (3–5). However, the role of these particles in the increased atherosclerotic risk associated with type 1 diabetes is unclear. No studies to date have examined apolipoprotein (apo)B48, a specific marker of chylomicron particle number, in the human type 1 diabetic population.

Nine normolipidemic subjects (five male and four female) with brittle type 1 diabetes and seven healthy normolipidemic …
Evolutionary psychiatry is dead – Long liveth evolutionary psychopathology
Authors: Martin Brüne
Journal: Behavioral and Brain Sciences (2006)

Keller &amp; Miller (K&amp;M) propose that many psychiatric disorders are best explained in terms of a genetic watershed model. This view challenges traditional evolutionary accounts of psychiatric disorders, many of which have tried to argue in support of a presumed balanced polymorphism, implying some hidden adaptive advantage of the alleles predisposing people to psychiatric disorders. Does this mean that evolutionary ideas are no longer viable to explain psychiatric disorders? The answer is no . However, K&amp;M's critical evaluation supports the view that psychiatric disorders are not categorically distinct from normalcy, and that evolutionary psychopathology should be grounded in rigorous empirical testing.
Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter.
Authors: M J Abramowicz, H M Targovnik, V Varela, P Cochaux, L Krawiec, M A Pisarev, F V Propato, G Juvenal, H A Chester, G Vassart
Journal: Journal of Clinical Investigation (1992)

Thyroid peroxidase (TPO) is the key enzyme in the synthesis of thyroid hormones, and the TPO defects are believed to be the most prevalent causes of the inborn errors of thyroid metabolism. We investigated an adopted boy with iodide organification defect, who presented with florid hypothyroidism at the age of 4 mo, poorly complied with thyroxine treatment, and developed a compressive goiter necessitating partial resection at the age of 12 yr. Biochemical studies revealed the absence of TPO activity in the resected tissue. Genomic DNA studies identified a 4 base-pair insertion in the eighth exon of the TPO gene, and showed that the patient was homozygous for this frameshift mutation. The direct genetic diagnosis of this mutation can be made by digestion of polymerase chain reaction products with NaeI restriction enzyme. This will help assessing its prevalence among the heterogenous genetic group of TPO defects.
Consumer advertising and doctors' prescribing
Authors: Peter Davies
Journal: BMJ (2005)

Modified Mediterranean diet and survival Evidence for diet linked longevity is substantialEditor-The EPIC-elderly cohort study was designed to investigate the association between a modified Mediterranean diet and longer life expectancy among an elderly subpopulation (older than 60) that is part of the larger EPIC (European Prospective Investigation into Cancer and Nutrition) cohort. 1 2 Focusing the attention on a sample with a more restricted age range seems to reinforce previous findings on diet linked longevity, but important risk factors were not taken into account in collecting the data.Total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, and blood pressure are well known determinants of cardiovascular disease.The study's outcomes are expressed in term of mortality, and cardiovascular disease remains the most important of all causes of death.The benefits of a healthy eating pattern with respect to these variables have been shown. 3he same might not be sustained if the total EPIC cohort were considered (aged 20-85). 2 Have the authors considered any possible statistical gain from including these risk factors in the analysis when considering the younger subgroup?We believe that the conclusions for participants older than 60 are stronger if the risk of cardiovascular disease in men and women after the menopause is considered.In a world in which people eat mainly processed foods that are rich in saturated fats, the analysis is a warning to adopt a healthier dietary pattern and, broadly, lifestyle changes.
Evidence on the Benefits and Harms of Screening and Treating Pregnant Women Who Are Asymptomatic for Bacterial Vaginosis: An Update Review for the U.S. Preventive Services Task Force
Authors: Peggy Nygren, Rongwei Fu, Michele Freeman, Christina Bougatsos, Mark Klebanoff, Jeanne-Marie Guise
Journal: Annals of Internal Medicine (2008)

Background: Bacterial vaginosis is the most common lower genital tract syndrome among women of reproductive age. There has been continued debate about the value of screening and treating asymptomatic pregnant women for bacterial vaginosis. Purpose: To examine new evidence on the benefits and harms of screening and treating bacterial vaginosis in asymptomatic pregnant women. Data Sources: English-language studies on Ovid MEDLINE (2000 to September 2007) and Cochrane Library databases (through September 2007), reference lists, and expert suggestions. Study Selection: Screening, treatment, or adverse effect studies with pregnancy outcome data in women who are asymptomatic for bacterial vaginosis. Data Extraction: Study and patient characteristics, treatment variables, adverse pregnancy outcomes, and internal validity quality criteria from the U.S. Preventive Services Task Force (USPSTF) and Jadad scale were abstracted. Data Synthesis: 7 new randomized, controlled treatment trials and 2001 report data were combined in a series of meta-analyses to estimate the pooled effect of treatment on preterm delivery (<37, <34, and <32 weeks); low birthweight; and preterm, premature rupture of membranes. Limitations: No screening studies that compared a screened population with a nonscreened population were found. Significant heterogeneity was found among the high-risk treatment trials (P < 0.001). It is not clear from the detailed description of the studies which factors explain the differences in preterm delivery rates and potentially the association of treatment effect; however, both raise concern for the unintended potential for harm. Conclusion: No benefit was found in treating women with low- or average-risk pregnancies for asymptomatic bacterial vaginosis. More research is needed to better understand these groups and the conditions under which treatment can be harmful or helpful, and to explore the relevance of bacterial vaginosis to other adverse pregnancy outcomes, such as delivery before 34 weeks.
A new device for in vivo measurement of nasal transepithelial potential difference in cystic fibrosis patients and normal subjects
Authors: O Duperrex, P Y Berclaz, D Bertrand, J S Lacroix, N Pochon, D Belli, T Rochat
Journal: European Respiratory Journal (1997)

Measurement of transepithelial potential difference (PD) on the nasal mucosa has been proposed to test for defective ion transport in cystic fibrosis (CF), and its possible correction after gene therapy or other treatments. The "classical" method records nasal PD under the inferior turbinate, with the disadvantage that the tip of the electrode is not seen by the operator. We have developed a purpose-designed perfusion electrode for PD recording on the visible, medial/posterior aspect of the turbinate. We wanted to determine whether such PD recordings adequately discriminate between CF patients and normal subjects. Measurements of baseline PD and response to a standardized perfusion protocol were performed in 20 normal subjects and 12 CF patients. Solutions of amiloride, with or without low chloride buffer were applied for 3 min. Increased baseline PD and depolarization after amiloride discriminated CF patients from normal subjects. Only one CF patient overlapped with the normal range. Superfusion of low chloride buffer with amiloride and terbutaline caused repolarization in 18 out of 20 normal subjects (90%), consistent with physiological Cl- secretion process, but in none of the CF patients. We conclude that measurements of potential difference on the medial/posterior aspect of the turbinate can discriminate between cystic fibrosis patients and normal subjects. At this site, visual control of the measurement is possible, and the mucosa is easily accessible for subsequent cytological sampling or biopsy.