tbuckley/cabot-search huggingface dataset:
Thigh circumference and risk of heart disease and premature death: prospective cohort study
Authors: B. L Heitmann, P. Frederiksen
Journal: BMJ (2009)

<b>Objective</b> To examine associations between thigh circumference and incident cardiovascular disease and coronary heart disease and total mortality. <b>Design</b> Prospective observational cohort study with Cox proportional hazards model and restricted cubic splines. <b>Setting</b> Random subset of adults in Denmark. <b>Participants</b> 1436 men and 1380 women participating in the Danish MONICA project, examined in 1987-8 for height, weight, and thigh, hip, and waist circumference, and body composition by impedance. <b>Main outcome measures</b> 10 year incidence of cardiovascular and coronary heart disease and 12.5 years of follow-up for total death. <b>Results</b> A small thigh circumference was associated with an increased risk of cardiovascular and coronary heart diseases and total mortality in both men and women. A threshold effect for thigh circumference was evident, with greatly increased risk of premature death below around 60 cm. Above the threshold there seemed to be no additional benefit of having larger thighs in either sex. These findings were independent of abdominal and general obesity, lifestyle, and cardiovascular risk factors such as blood pressure and lipid concentration. <b>Conclusion</b> A low thigh circumference seems to be associated with an increased risk of developing heart disease or premature death. The adverse effects of small thighs might be related to too little muscle mass in the region. The measure of thigh circumference might be a relevant anthropometric measure to help general practitioners in early identification of individuals at an increased risk of premature morbidity and mortality.
Advertising Campaign Puts Face on Prostate Cancer
Authors: Brian Vastag
Journal: JNCI Journal of the National Cancer Institute (2006)

Advertising Campaign Puts Face on Prostate CancerMeet Prosty the Spokesgland.The plucky prostate recently debuted on Capitol Hill, starring in a television advertisement designed to rally support for research into effective imaging tests for prostate cancer." Women have the mammogram, " said Faina Shtern, M.D., president and chief executive offi cer of the nonprofi t Ad-MeTech Foundation, which organized the October press event." Men want to know, ' Where is our man-o-gram?' " Last year AdMeTech, which Shtern founded in 2000, decided to focus on drawing philanthropy and government funding dedicated to prostate cancer imaging research.The foundation received Department of Defense grants in 2000 and 2002, which it used to fund research into molecular tags that could highlight incipient prostate tumors." We want to convince Congress that funding in this area is vital, " said Shtern, the former chief of the diagnostic imaging research branch at the National Cancer Institute.The Prosty campaign personifi es the problem as Shtern and her coalition see it.After the gland gets poked by a gloved fi nger and pierced by biopsy needles, he spins around and points to a throbbing red pustule on his backside." Hey, you missed a cancer!" he protests.Shtern's coalition also wants to reduce the number of biopsies that men undergo." The number of unnecessary biopsies is staggering, " she said.
Respiratory infections and the autumn increase in asthma morbidity
Authors: RE Dales, I Schweitzer, JH Toogood, M Drouin, W Yang, J Dolovich, J Boulet
Journal: European Respiratory Journal (1996)

Unexplained autumn increases in hospital admissions for asthma have been reported in many countries, including the United States, Canada, England and Wales. To investigate the role of infection, the association was tested between hospital admissions for asthma and respiratory infections among preschool children in Metropolitan Toronto, Canada during the period 1981 to 1989. The seasonal pattern in overall hospital utilization was assessed by admissions for nonrespiratory diseases. Time series analysis was used to remove potentially confounding temporal trends and the influence of correlated errors. A fourfold increase in asthma admissions occurred between July and October unaccompanied by similar increases in nonrespiratory admissions. Admissions began increasing during the third week of August, peaked during the third week in September, and slowly decreased during November and December. After adjusting for serial correlation, trends, climate, ambient air pollution and aeroallergens, the seasonal pattern of respiratory infection explained 14% of the variance in asthma admissions. Based on seasonal patterns, respiratory infection is the major identifiable risk factor for the large autumnal increase in asthma admissions.
Antigenic domains of the streptococcal Pep M5 protein. Localization of epitopes crossreactive with type 6 M protein and identification of a hypervariable region of the M molecule.
Authors: B N Manjula, A S Acharya, T Fairwell, V A Fischetti
Journal: The Journal of Experimental Medicine (1986)

Pep M5, the pepsin-derived N-terminal half of the group A streptococcal type 5 M protein exhibits immunologic crossreaction with type 6 M protein, localizing some of the M6-crossreactive epitope(s) within this segment of the M5 protein. Based on the amino acid sequence of the Pep M5 protein, two structurally distinct domains have been recognized within its coiled-coil structure. We have now found that peptides derived from both the structurally distinct domains of the Pep M5 protein contain antigenic epitopes. Furthermore, only the peptides from the C-terminal domain of the Pep M5 protein crossreacted with rabbit anti-M6 sera, whereas those from the N-terminal domain did not. Consistent with this, sequence analyses of the arginyl peptides of the Pep M6 protein, the pepsin-derived N-terminal half of the M6 protein, revealed extensive homology of some of these peptides with regions within the C-terminal domain of the Pep M5 molecule. While an arginyl peptide of the Pep M6 protein exhibits 84% homology with region 150-186 of the Pep M5 protein, the C-terminal hexadecapeptide of the Pep M6 protein is virtually identical with the corresponding region of the Pep M5 protein. These results are suggestive of conformational similarities in the region around the pepsin-susceptible site within the M5 and M6 proteins. In addition, one or more epitopes of the M5 protein that are crossreactive with the M6 protein may be placed close to the pepsin-susceptible site of the M5 protein. Previous studies have suggested the N-terminal half of the M proteins to be the variable part of the molecule among the different M protein serotypes. The present results suggest that the N-terminal quarter of the M protein may represent the hypervariable domain of the M molecule.
Asymmetric dimethylarginine and asthma: results from the Childhood Asthma Prevention Study
Authors: Edmund M.T. Lau, Philip E. Morgan, Elena G. Belousova, Brett G. Toelle, Julian G. Ayer, David S. Celermajer, Guy B. Marks
Journal: European Respiratory Journal (2013)

To the Editor: 

Asymmetric dimethylarginine (ADMA) is a naturally occurring analogue of l-arginine and functions as an endogenous inhibitor of nitric oxide synthase (NOS). ADMA is an established risk factor for cardiovascular disease and contributes to chronic endothelial dysfunction [1]. Recently, it has been proposed that ADMA is also a mediator of allergic airways disease, with animal studies indicating a possible role in the development of airway hyperresponsiveness, lung inflammation and fibrosis. Exogenous administration of ADMA has been shown to augment airway responsiveness to methacholine in murine models of asthma and increased ADMA levels were observed in lung homogenates and sputum specimens from humans with asthma [2]. However, human data on the relationship between ADMA and asthma are limited. Therefore, we examined the relationship between systemic ADMA levels and current asthma in a cohort from the Childhood Asthma Prevention Study (CAPS).

Study subjects included 314 8-year-old children from Sydney, Australia. They were originally enrolled prenatally into a randomised controlled trial of house dust mite avoidance and dietary fatty acid modification implemented from birth to 5 years. All subjects had one or more parents or an older sibling with asthma or wheezing illness. The details of this trial have been published elsewhere [3]. Of the 616 subjects who were enrolled prenatally, 314 had clinical and laboratory data available for analysis at age 8 years for the present study. The study was approved by the local human research ethics committee and the parent or legal guardian gave written informed consent.

Current asthma at 8 years of age was …
Apolipoprotein AIV Gene Variant S347 Is Associated With Increased Risk of Coronary Heart Disease and Lower Plasma Apolipoprotein AIV Levels
Authors: Wai-man R. Wong, Emma Hawe, Lai K. Li, George J. Miller, Viviane Nicaud, Len A. Pennacchio, Steve E. Humphries, Philippa J. Talmud
Journal: Circulation Research (2003)

The impact of common variants in the apolipoprotein gene cluster ( APOC3-A4-A5 ) on prospective coronary heart disease (CHD) risk was examined in healthy UK men. Of the 2808 men followed over 9 years, 187 had a clinically defined CHD event. Examination of 9 single nucleotide polymorphisms (SNPs) in this group revealed that homozygotes for APOA4 S347 had significantly increased risk of CHD [hazard ratio (HR) of 2.07 (95%CI 1.04 to 4.12)], whereas men homozygous for APOC3 1100T were protected [HR 0.28 (95%CI 0.09 to 0.87)]. In stepwise multiple regression analysis, after entering all the variants and adjusting for established risk factors APOA4 T347S alone remained in the model. Using all nine SNPs, the highest risk-estimate haplotypes carried APOA4 S347 and rare alleles of the two flanking intergenic markers. The protective effect of APOC3 1100T could be explained by negative linkage disequilibrium with these alleles. To determine the association of APOA4 T347S with apoAIV levels, the relationship was examined in 1600 healthy young European men and women. S347 homozygotes had significantly lower apoAIV plasma levels (13.64±0.59 mg/dL) compared with carriers of the T347 allele (14.90±0.12 mg/dL) ( P =0.035). These results demonstrate that genetic variation in and around APOA4 , independent of the effects of triglyceride, is associated with risk of CHD and apoAIV levels, supporting an antiatherogenic role for apoAIV.
Pancreatitis-associated chymotrypsinogen C (CTRC) mutant elicits endoplasmic reticulum stress in pancreatic acinar cells
Authors: R. Szmola, M. Sahin-Toth
Journal: Gut (2009)

<h3>Objective</h3> Chronic pancreatitis is a progressive inflammatory disorder of the pancreas characterised by permanent destruction of acinar cells. Mutations in the chymotrypsinogen C (<i>CTRC</i>) gene have been linked to the development of chronic pancreatitis. The aim of the present study was to explore whether CTRC mutants induce endoplasmic reticulum (ER) stress in pancreatic acinar cells. <h3>Design</h3> Dexamethasone-differentiated AR42J rat acinar cells and freshly isolated mouse acini were transfected with recombinant adenovirus carrying wild-type CTRC or the p.A73T pancreatitis-associated mutant. ER stress markers were assessed by reverse transcription-PCR and western blotting. Apoptosis was characterised by caspase-3/7 activity and the TUNEL assay. <h3>Results</h3> Acinar cells transfected with the p.A73T mutant, but not those with wild-type CTRC, developed significant ER stress as judged by elevated mRNA and protein levels of the ER chaperone immunoglobulin-binding protein (BiP), increased splicing of the X-box binding protein-1 (XBP1) mRNA and marked induction of the transcription factor C/EBP-homologous protein (CHOP), a mediator of ER stress-associated apoptosis. Consistent with higher CHOP expression, AR42J cells expressing the p.A73T mutant became detached over time and showed considerably increased caspase-3/7 activity and TUNEL staining. <h3>Conclusions</h3> Pancreatitis-associated <i>CTRC</i> mutations can markedly increase the propensity of chymotrypsinogen C to elicit ER stress in pancreatic acinar cells. Thus, carriers of <i>CTRC</i> mutations may be at a higher risk of developing ER stress in the exocrine pancreas, which may contribute to parenchymal damage through acinar cell apoptosis.
Attenuation of Hypoxic Pulmonary Vasoconstriction by Endotoxemia Requires 5-Lipoxygenase in Mice
Authors: Fumito Ichinose, Warren M. Zapol, Adam Sapirstein, Roman Ullrich, Andrew M. Tager, Kenneth Coggins, Rosemary Jones, Kenneth D. Bloch
Journal: Circulation Research (2001)

Abstract —Sepsis and endotoxemia impair hypoxic pulmonary vasoconstriction (HPV), thereby reducing systemic oxygenation. To assess the role of leukotrienes (LTs) in the attenuation of HPV during endotoxemia, the increase in left lung pulmonary vascular resistance (LPVR) before and during left mainstem bronchus occlusion (LMBO) was measured in mice with and without a deletion of the gene encoding 5-lipoxygenase (5-LO). LMBO increased the LPVR equally in saline-challenged wild-type and 5-LO–deficient mice (96±20% and 94±19%, respectively). Twenty-two hours after challenge with Escherichia coli endotoxin, the ability of LMBO to increase LPVR was markedly impaired in wild-type mice (27±7%; P &lt;0.05) but not in 5-LO–deficient mice (72±9%) or in wild-type mice pretreated with MK886, an inhibitor of 5-LO activity (76±10%). Compared with wild-type mice, endotoxin-induced disruption of lung structures and inflammatory cell influx in the lung were markedly attenuated in 5-LO–deficient mice. Administration of MK571, a selective cysteinyl LT 1 receptor antagonist, 1 hour before endotoxin challenge preserved HPV and attenuated pulmonary injury in wild-type mice but did not prevent the endotoxin-induced increase in pulmonary myeloperoxidase activity. Taken together, these findings demonstrate that a 5-LO product, most likely a cysteinyl LT, contributes to the attenuation of HPV and to pulmonary injury after challenge with endotoxin.
Effect of antidepressant drug counselling and information leaflets on adherence to drug treatment in primary care: randomised controlled trial
Authors: R. Peveler, C. George, A.-L. Kinmonth, M. Campbell, C. Thompson
Journal: BMJ (1999)

<h3>Abstract</h3> <b>Objectives:</b> To evaluate two different methods of improving adherence to antidepressant drugs. <b>Design:</b> Factorial randomised controlled single blind trial of treatment leaflet, drug counselling, both, or treatment as usual. <b>Setting:</b> Primary care in Wessex <b>Participants:</b> 250 patients starting treatment with tricyclic antidepressants. <b>Main outcome measures:</b> Adherence to drug treatment (by confidential self report and electronic monitor); depressive symptoms and health status. <b>Results:</b> 66 (63%) patients continued with drugs to 12 weeks in the counselled group compared with 42 (39%) of those who did not receiving counselling (odds ratio 2.7, 95% confidence interval 1.6 to 4.8; number needed to treat=4) Treatment leaflets had no significant effect on adherence. No differences in depressive symptoms were found between treatment groups overall, although a significant improvement was found in patients with major depressive disorder receiving drug doses of at least 75 mg (depression score 4 (SD 3.7) counselling <i>v</i> 5.9 (SD 5.0) no counselling, P=0.038). <b>Conclusions:</b> Counselling about drug treatment significantly improved adherence, but clinical benefit was seen only in patients with major depressive disorder receiving doses ≥75 mg. Further research is required to evaluate the effect of this approach in combination with appropriate targeting of treatment and advice about dosage. <h3>Key messages</h3> Non-adherence is a serious problem in the treatment of depression by general practitioners In this study a brief psychosocial intervention delivered by a nurse greatly improved adherence Clinical benefit was apparent only in patients with major depressive episodes on higher doses of drugs Counselling should be targeted at patients with symptoms of at least moderate severity and combined with therapeutic drug doses
The chemokine receptor CXCR4 is expressed in pancreatic intraepithelial neoplasia
Authors: R M Thomas, J Kim, M P Revelo-Penafiel, R Angel, D W Dawson, A M Lowy
Journal: Gut (2008)

<h3>Objective:</h3> The chemokine CXCL12, together with its specific receptor, CXCR4, have been shown to mediate invasiveness and metastatic behaviour in pancreatic cancer cells. The expression of CXC12/CXCR4 has not been previously examined in pancreatic intraepithelial neoplasias (PanIN), the accepted precursor lesions to pancreatic duct cancer. <h3>Design:</h3> In this study we sought to characterise the expression of CXCL12 and CXCR4 during the progression of PanIN using both a murine model and human tissues. <h3>Results:</h3> These studies reveal that both CXCL12 and CXCR4 are expressed in PanIN and that the frequency increases during PanIN progression (0% CXCR4 expression in normal mouse and human ducts vs 100% in mouse PanIN 3 and 77% in human PanIN 3). Next we demonstrate a dose-dependent increase in the proliferation of murine PanIN cells when exposed to CXCL12. Finally, we show that expression of CXCR4 in murine PanIN cells is partially dependent on mitogen-activated protein kinase (MAPK) signalling and that the effect of CXCL12 on PanIN proliferation can be abrogated by an MAPK inhibitor. <h3>Conclusions:</h3> Together these results demonstrate that CXCL12/CXCR4 expression begins in the pre-invasive stages of pancreatic neoplasia, and suggest that the presence of an autocrine loop that is at least partially regulated by MAPK signalling. Further studies that define the role of CXCR4 signalling in PanIN progression will determine if CXCR4 could serve as a novel target for chemoprevention and early stage therapy in pancreatic cancer.
Coordinated Cancer Germline Antigen Promoter and Global DNA Hypomethylation in Ovarian Cancer: Association with the <i>BORIS/CTCF</i> Expression Ratio and Advanced Stage
Authors: Anna Woloszynska-Read, Wa Zhang, Jihnhee Yu, Petra A. Link, Paulette Mhawech-Fauceglia, Golda Collamat, Stacey N. Akers, Kelly R. Ostler, Lucy A. Godley, Kunle Odunsi, Adam R. Karpf
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Cancer germline (CG) antigens are frequently expressed and hypomethylated in epithelial ovarian cancer (EOC), but the relationship of this phenomenon to global DNA hypomethylation is unknown. In addition, the potential mechanisms leading to DNA hypomethylation, and its clinicopathologic significance in EOC, have not been determined. Experimental Design: We used quantitative mRNA expression and DNA methylation analyses to determine the relationship between expression and methylation of X-linked (MAGE-A1, NY-ESO-1, XAGE-1) and autosomal (BORIS, SOHLH2) CG genes, global DNA methylation (5mdC levels, LINE-1, Alu, and Sat-α methylation), and clinicopathology, using 75 EOC samples. In addition, we examined the association between these parameters and a number of mechanisms proposed to contribute to DNA hypomethylation in cancer. Results: CG genes were coordinately expressed in EOC and this was associated with promoter DNA hypomethylation. Hypomethylation of CG promoters was highly correlated and strongly associated with LINE-1 and Alu methylation, moderately with 5mdC levels, and rarely with Sat-α methylation. BORIS and LINE-1 hypomethylation, and BORIS expression, were associated with advanced stage. GADD45A expression, MTHFR genotype, DNMT3B isoform expression, and BORIS mRNA expression did not associate with methylation parameters. In contrast, the BORIS/CTCF expression ratio was associated with DNA hypomethylation, and furthermore correlated with advanced stage and decreased survival. Conclusions: DNA hypomethylation coordinately affects CG antigen gene promoters and specific repetitive DNA elements in EOC, and correlates with advanced stage disease. The BORIS/CTCF mRNA expression ratio is closely associated with DNA hypomethylation and confers poor prognosis in EOC. Clin Cancer Res; 17(8); 2170–80. ©2011 AACR.
Class I dependence of the development of CD4+ CD8- NK1.1+ thymocytes.
Authors: M C Coles, D H Raulet
Journal: The Journal of Experimental Medicine (1994)

A small subset of functionally active CD4+ CD8- thymocytes express the NK1.1 marker, as do most CD4-CD8- NK1.1+ thymocytes. Previous studies have failed to implicate a role for major histocompatibility complex (MHC) or related molecules in the selection of the CD4+ CD8- NK1.1+ subset. We report here that the development of most of these cells is sharply reduced in class I-deficient mice, but not in class II-deficient mice. Hence, some CD4+ T cells are class I dependent and not class II dependent. Unlike conventional T cells, however, the development of NK1.1+ thymocytes in both the CD4+ CD8- and CD4- CD8- subsets is dependent on class I MHC expression by hematopoietic cells and not thymic epithelial cells. We propose that these populations are selected by nonpolymorphic class Ib or CD1 molecules.
Enzymatic Self-Assembly of Nanostructures for Theranostics
Authors: Yue Chen, Gaolin Liang
Journal: Theranostics (2012)

Self-assembly of small molecules or macromolecules through non-covalent or covalent bonds to build up supramolecular nanostructures is a prevalent and important process in nature. While most chemists use small molecules to assemble nanostructures with physical or chemical perturbations, nature adopts enzymes to catalyze the reaction to assemble biological, functional nanostructures with high efficiency and specificity. Although enzymatic self-assembly of nanostructures has been remained challenging for chemists, there are still a few examples of using important enzymes to initiate the self-assembly of nanostructures for diagnosis or therapy of certain diseases because down-regulation or overexpression of certain enzymes always associates with abnormalities of tissues/organs or diseases in living body. Herein, we introduce the concept of enzymatic self-assembly and illustrate the design and application of enzyme-catalyzed or -regulated formation of nanostructures for theranostics.