bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of the protein Z ATG haplotype with symptomatic nonvascular stroke or thromboembolism in white children: a family-based cohort study
Authors: Nowak-Göttl Ulrike , Fröhlich Birgit , Thedieck Sabine , Huge Andreas , Stoll Monika 
Published: December 2008

Abstract
To clarify the role of protein Z (PZ) in children with stroke/thromboembolism (TE), the present haplotype (HT)–based family study was performed. We genotyped 365 pediatric stroke/TE families (stroke n = 216; TE n = 149) for 4 single nucleotide polymorphisms (SNPs; rs3024718, rs3024731, rs3024772, and rs3024778) to assess the association between genetic variation within a conserved block of linkage disequilibrium harboring the PZ gene and pediatric TE. Association was assessed with use of the transmission disequilibrium test (TDT), corrected for multiple testing (permutation testing: HAPLOVIEW). In addition, PZ antigen was determined and correlated with carriership of PZ haplotypes and the FV G1691A mutation. Rs3024718, rs3024731, and rs3024772 are in tight linkage disequilibrium (LD) and define 4 haplotypes, capturing 97% of the genetic variation for this LD block. HT1 (ATG) was significantly overtransmitted from parents to affected offspring (HT frequency 73.5%, T:U 122:80, χ2 = 8.791, P = .003). The ATG risk haplotype was significantly correlated with greater PZ antigen levels. Multivariate analysis adjusted for age, sex, established thrombophilias, smoking, fibrinogen, and PZ levels revealed a significant association of the ATG haplotype and TE in children (odds ratio [OR] 1.4; 95% confidence interval [95% CI] 1.08-1.93). Our results suggest that the ATG haplotype of the PZ gene is a genetic marker for symptomatic TE in white German children.
Relationship between ventilatory constraint and muscle fatigue during exercise in COPD
Authors: Butcher S. J. , Lagerquist O. , Marciniuk D. D. , Petersen S. R. , Collins D. F. , Jones R. L. 
Published: December 2008

Dynamic hyperinflation and leg muscle fatigue are independently associated with exercise limitation in patients with chronic obstructive pulmonary disease (COPD). The aims of the present study were to examine 1) the relationship between these limitations and 2) the effect of delaying ventilatory limitation on exercise tolerance and leg muscle fatigue.In total, 11 patients with COPD (with a forced expiratory volume in one second of 52% predicted) completed two cycling bouts breathing either room air or heliox, and one bout breathing heliox but stopping at room air isotime. End-expiratory lung volume (EELV), leg muscle fatigue and exercise time were measured.On room air, end-exercise EELV was negatively correlated with leg fatigue. Heliox increased exercise time (from 346 to 530 s) and leg fatigue (by 15%). At isotime, there was no change in leg fatigue, despite a reduction in EELV compared with end-exercise, in both room air and heliox. The change in exercise time with heliox was best correlated with room air leg fatigue and end-inspiratory lung volume.Patients with chronic obstructive pulmonary disease who had greater levels of dynamic hyperinflation on room air had less muscle fatigue. These patients were more likely to increase exercise tolerance with heliox, which resulted in greater leg muscle fatigue.
Reduced risk of next exacerbation and mortality associated with antibiotic use in COPD
Authors: Roede B. M. , Bresser P. , Prins J. M. , Schellevis F. , Verheij T. J. M. , Bindels P. J. E. 
Published: December 2008

The long-term risk of a subsequent exacerbation of chronic obstructive pulmonary disease (COPD) after treatment with oral corticosteroids without (OS) or with antibiotics (OSA) was compared in a historical general practice-based cohort.Eligible patients were ≥50 yrs of age, had a registered diagnosis of COPD, were on maintenance respiratory drugs, and had experienced at least one exacerbation defined as a prescription OS or OSA. Times to second and third exacerbations were assessed using Kaplan–Meier survival analysis; the risk of a subsequent exacerbation was assessed in a Cox proportional hazards analysis; and all-cause mortality was assessed using Kaplan–Meier survival and Cox proportional hazards analyses.A total of 842 patients had one or more exacerbations. The median time from first to second exacerbation was comparable for the OS and OSA groups, but the time from second to third exacerbation differed: 189versus258 days, respectively. The protective effect of OSA was most pronounced during the first 3 months following treatment (hazards ratio 0.72, 95% confidence interval 0.62–0.83). Exposure to antibiotics unrelated to a course of oral corticosteroids almost halved the risk of a new exacerbation. Mortality during follow-up was considerably lower in the OSA group.Adding antibiotics to oral corticosteroids was associated with: reduced risk of subsequent exacerbation, particularly in patients with recurrent exacerbations; and reduced risk of all-cause mortality.
Sex differences in mortality in patients with COPD
Authors: de Torres J. P. , Cote C. G. , López M. V. , Casanova C. , Díaz O. , Marin J. M. , Pinto-Plata V. , de Oca M. M. , Nekach H. , Dordelly L. J. , Aguirre-Jaime A. , Celli B. R. 
Published: December 2008

Little is known about survival and clinical prognostic factors in females with chronic obstructive pulmonary disease (COPD). The aim of the present study was to determine the survival difference between males and females with COPD and to compare the value of the different prognostic factors for the disease.In total, 265 females and 272 males with COPD matched at baseline by BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) and American Thoracic Society/European Respiratory Society/Global Initiative of Chronic Obstructive Lung Disease criteria were prospectively followed. Demographics, lung function, St George’s Respiratory Questionnaire, BODE index, the components of the BODE index and comorbidity were determined. Survival was documented and sex differences were determined using Kaplan–Meier analysis. The strength of the association of the studied variables with mortality was determined using multivariate and receiver operating curves analysis.All-cause (40versus18%) and respiratory mortality (24versus10%) were higher in males than females. Multivariate analysis identified the BODE index in females and the BODE index and Charlson comorbidity score in males as the best predictors of mortality. The area under the curve of the BODE index was a better predictor of mortality than the forced expiratory volume in one second for both sexes.At similar chronic obstructive pulmonary disease severity by BODE index and forced expiratory volume in one second, females have significantly better survival than males. For both sexes the BODE index is a better predictor of survival than the forced expiratory volume in one second.
Circulating cell-derived microparticles in patients with minimally symptomatic obstructive sleep apnoea
Authors: Ayers L. , Ferry B. , Craig S. , Nicoll D. , Stradling J. R. , Kohler M. 
Published: December 2008

Moderate–severe obstructive sleep apnoea (OSA) has been associated with several pro-atherogenic mechanisms and increased cardiovascular risk, but it is not known if minimally symptomatic OSA has similar effects. Circulating cell-derived microparticles have been shown to have pro-inflammatory, pro-coagulant and endothelial function-impairing effects, as well as to predict subclinical atherosclerosis and cardiovascular risk.In 57 patients with minimally symptomatic OSA, and 15 closely matched control subjects without OSA, AnnexinV-positive, platelet-, leukocyte- and endothelial cell-derived microparticles were measured by flow cytometry.In patients with OSA, median (interquartile range) levels of AnnexinV-positive microparticles were significantly elevated compared with control subjects: 2,586 (1,566–3,964) μL−1versus1,206 (474–2,501) μL−1, respectively. Levels of platelet-derived and leukocyte-derived microparticles were also significantly higher in patients with OSA (2,267 (1,102–3,592) μL−1and 20 (14–31) μL−1, respectively) compared with control subjects (925 (328–2,068) μL−1and 15 (5–23) μL−1, respectively). Endothelial cell-derived microparticle levels were similar in patients with OSA compared with control subjects (13 (8–25) μL−1versus11 (6–17) μL−1).In patients with minimally symptomatic obstructive sleep apnoea, levels of AnnexinV-positive, platelet- and leukocyte-derived microparticles are elevated when compared with closely matched control subjects without obstructive sleep apnoea. These findings suggest that these patients may be at increased cardiovascular risk, despite being minimally symptomatic.
Inference of haplotypic phase and missing genotypes in polyploid organisms and variable copy number genomic regions
Authors: Su Shu-Yi , White Jonathan , Balding David J , Coin Lachlan JM 
Published: December 2008

Abstract

Background
The power of haplotype-based methods for association studies, identification of regions under selection, and ancestral inference, is well-established for diploid organisms. For polyploids, however, the difficulty of determining phase has limited such approaches. Polyploidy is common in plants and is also observed in animals. Partial polyploidy is sometimes observed in humans (e.g. trisomy 21; Down's syndrome), and it arises more frequently in some human tissues. Local changes in ploidy, known as copy number variations (CNV), arise throughout the genome. Here we present a method, implemented in the software polyHap, for the inference of haplotype phase and missing observations from polyploid genotypes. PolyHap allows each individual to have a different ploidy, but ploidy cannot vary over the genomic region analysed. It employs a hidden Markov model (HMM) and a sampling algorithm to infer haplotypes jointly in multiple individuals and to obtain a measure of uncertainty in its inferences.

Results
In the simulation study, we combine real haplotype data to create artificial diploid, triploid, and tetraploid genotypes, and use these to demonstrate that polyHap performs well, in terms of both switch error rate in recovering phase and imputation error rate for missing genotypes. To our knowledge, there is no comparable software for phasing a large, densely genotyped region of chromosome from triploids and tetraploids, while for diploids we found polyHap to be more accurate than fastPhase. We also compare the results of polyHap to SATlotyper on an experimentally haplotyped tetraploid dataset of 12 SNPs, and show that polyHap is more accurate.

Conclusion
With the availability of large SNP data in polyploids and CNV regions, we believe that polyHap, our proposed method for inferring haplotypic phase from genotype data, will be useful in enabling researchers analysing such data to exploit the power of haplotype-based analyses.
Systematic review of the relation between smokeless tobacco and cancer of the pancreas in Europe and North America
Authors: Sponsiello-Wang Zheng , Weitkunat Rolf , Lee Peter N 
Published: December 2008

Abstract

Background
Recent reviews claiming smokeless tobacco increases pancreatic cancer risk appear not to have considered all available epidemiological evidence; nor were meta-analyses included. We present a systematic review of studies from North America and Europe, since data are lacking from other continents. Risk is also difficult to quantify elsewhere due to the various products, compositions and usage practices involved.

Methods
Epidemiological studies were identified that related pancreatic cancer to use of snuff, chewing tobacco or unspecified smokeless tobacco. Study details and effect estimates (relative risks or odds ratios) were extracted, and combined by meta-analyses.

Results
Nine North American and two Scandinavian studies were identified. Reporting was limited in four studies, so only seven were included in meta-analyses, some providing results for never smokers, some for the overall population of smokers and non-smokers, and some for both.
Giving preference to study-specific estimates for the overall population, if available, and for never smokers otherwise, the random-effects estimate for ever smokeless tobacco use was 1.03 (95% confidence interval 0.71–1.49) based on heterogeneous estimates from seven studies. The estimate varied little by continent, study type, or type of smokeless tobacco.
Giving preference to estimates for never smokers, if available, and overall population estimates otherwise, the estimate was 1.14 (0.67–1.93), again based on heterogeneous estimates. Estimates varied (p = 0.014) between cohort studies (1.75, 1.20–2.54) and case-control studies (0.84, 0.36–1.97). The value for cohort studies derived mainly from one study, which reported an increase for never smokers (2.0, 1.2–3.3), but not overall (0.9, 0.7–1.2). This study also contributed to increases seen for snuff use and for European studies, significant only in fixed-effect analyses.
The studies have various weaknesses, including few exposed cases, reliance in cohort studies on exposure recorded at baseline, poor control groups in some case-control studies, and lack of a dose-response. Publication bias, with some negative studies not being presented, is also possible.

Conclusion
At most, the data suggest a possible effect of smokeless tobacco on pancreatic cancer risk. More evidence is needed. If any risk exists, it is highly likely to be less than that from smoking.
Hepatic steatosis in n-3 fatty acid depleted mice: focus on metabolic alterations related to tissue fatty acid composition
Authors: Pachikian BD , Neyrinck AM , Cani PD , Portois L , Deldicque L , De Backer FC , Bindels LB , Sohet FM , Malaisse WJ , Francaux M , Carpentier YA , Delzenne NM 
Published: December 2008

Abstract

Background
There are only few data relating the metabolic consequences of feeding diets very low in n-3 fatty acids. This experiment carried out in mice aims at studying the impact of dietary n-3 polyunsaturated fatty acids (PUFA) depletion on hepatic metabolism.

Results
n-3 PUFA depletion leads to a significant decrease in body weight despite a similar caloric intake or adipose tissue weight. n-3 PUFA depleted mice exhibit hypercholesterolemia (total, HDL, and LDL cholesterol) as well as an increase in hepatic cholesteryl ester and triglycerides content. Fatty acid pattern is profoundly modified in hepatic phospholipids and triglycerides. The decrease in tissue n-3/n-6 PUFA ratio correlates with steatosis. Hepatic mRNA content of key factors involved in lipid metabolism suggest a decreased lipogenesis (SREBP-1c, FAS, PPARγ), and an increased β-oxidation (CPT1, PPARα and PGC1α) without modification of fatty acid esterification (DGAT2, GPAT1), secretion (MTTP) or intracellular transport (L-FABP). Histological analysis reveals alterations of liver morphology, which can not be explained by inflammatory or oxidative stress. However, several proteins involved in the unfolded protein response are decreased in depleted mice.

Conclusion
n-3 PUFA depletion leads to important metabolic alterations in murine liver. Steatosis occurs through a mechanism independent of the shift between β-oxidation and lipogenesis. Moreover, long term n-3 PUFA depletion decreases the expression of factors involved in the unfolded protein response, suggesting a lower protection against endoplasmic reticulum stress in hepatocytes upon n-3 PUFA deficiency.
Pulmonary response to intratracheal instillation of ultrafine versus fine titanium dioxide: role of particle surface area
Authors: Sager Tina M , Kommineni C , Castranova Vincent 
Published: December 2008

Abstract

Background
The production and use of nanoparticles is growing rapidly due to the unique physical and chemical properties associated with their nano size and large surface area. Since nanoparticles have unique physicochemical properties, their bioactivity upon exposure to workers or consumers is of interest. In this study, the issue of what dose metric (mass dose versus surface area dose) is appropriate for toxicological studies has been addressed. Rats were exposed by intratracheal instillation to various doses of ultrafine or fine TiO2. At 1, 7, or 42 days post-exposure, inflammatory and cytotoxic potential of each particle type was compared on both a mass dosage (mg/rat) as well as an equal surface area dosage (cm2 of particles per cm2 of alveolar epithelium) basis.

Results
The findings of the study show that on a mass basis the ultrafine particles caused significantly more inflammation and were significantly more cytotoxic than the fine sized particles. However, when doses were equalized based on surface area of particles delivered, the ultrafine particles were only slightly more inflammogenic and cytotoxic when compared to the fine sized particles. Lung burden data indicate that ultrafine TiO2 appears to migrate to the interstitium to a much greater extent than fine TiO2.

Conclusion
This study suggests that surface area of particles may be a more appropriate dose metric for pulmonary toxicity studies than mass of particles.
Transfection of the mutant MYH9 cDNA reproduces the most typical cellular phenotype of MYH9-related disease in different cell lines
Authors: Panza Emanuele , Marini Monica , Pecci Alessandro , Giacopelli Francesca , Bozzi Valeria , Seri Marco , Balduini Carlo , Ravazzolo Roberto 
Published: December 2008

Abstract

Background
Heterozygous mutations of MYH9, encoding the Non-Muscular Myosin Heavy Chain-IIA (NMMHC-IIA), cause a complex disorder named MYH9-related disease, characterized by a combination of different phenotypic features. At birth, patients present platelet macrocytosis, thrombocytopenia and leukocyte inclusions containing NMMHC-IIA. Moreover, later in life some of them develop the additional features of sensorineural hearing loss, cataracts and/or glomerulonephritis that sometimes leads to end stage renal failure.

Results
To clarify the mechanism by which the mutant NMMHC-IIA could cause phenotypic anomalies at the cellular level, we examined the effect of transfection of the full-length mutated D1424H MYH9 cDNAs. We have observed, by confocal microscopy, abnormal distribution of the protein and formation of rod-like aggregates reminiscent of the leukocyte inclusions found in patients. Co-transfection of differently labeled wild-type and mutant full-length cDNAs showed the simultaneous presence of both forms of the protein in the intracellular aggregates.

Conclusion
These findings suggest that the NMMHC-IIA mutated in position 1424 is able to interact with the WT form in living cells, despite part of the mutant protein precipitates in non-functional aggregates. Transfection of the entire WT or mutant MYH9 in cell lines represents a powerful experimental model to investigate consequences of MYH9 mutations.
Abnormal mannose-6-phosphate receptor trafficking impairs recombinant alpha-glucosidase uptake in Pompe disease fibroblasts
Authors: Cardone Monica , Porto Caterina , Tarallo Antonietta , Vicinanza Mariella , Rossi Barbara , Polishchuk Elena , Donaudy Francesca , Andria Generoso , De Matteis Maria Antonietta , Parenti Giancarlo 
Published: December 2008

Abstract

Background
Pompe disease (PD) is a metabolic myopathy caused by α-glucosidase (GAA) deficiency and characterized by generalized glycogen storage. Heterogeneous GAA gene mutations result in wide phenotypic variability, ranging from the severe classic infantile presentation to the milder intermediate and late-onset forms. Enzyme replacement therapy (ERT) with recombinant human GAA (rhGAA), the only treatment available for PD, intriguingly shows variable efficacy in different PD patients. To investigate the mechanisms underlying the variable response to ERT, we studied cell morphology of PD fibroblasts, the distribution and trafficking of the cation-independent mannose-6-phosphate receptor (CI-MPR) that mediates rhGAA uptake, and rhGAA uptake itself.

Results
We observed abnormalities of cell morphology in PD cells. Electron microscopy analysis showed accumulation of multivesicular bodies and expansion of the Golgi apparatus, and immunolocalization and western blot analysis of LC3 showed activation of autophagy. Immunofluorescence analysis showed abnormal intracellular distribution of CI-MPR in PD fibroblasts, increased co-localization with LC3 and reduced availability of the receptor at the plasma membrane. The recycling of CI-MPR from the plasma membrane to the trans-Golgi network was also impaired. All these abnormalities were more prominent in severe and intermediate PD fibroblasts, correlating with disease severity. In severe and intermediate PD cells rhGAA uptake and processing were less efficient and correction of GAA activity was reduced.

Conclusion
These results indicate a role for disrupted CI-MPR trafficking in the variable response to ERT in PD and have implications for ERT efficacy and optimization of treatment protocols.
Retinoid X receptor and peroxisome proliferator-activated receptor-gamma agonists cooperate to inhibit matrix metalloproteinase gene expression
Authors: Burrage Peter S , Schmucker Adam C , Ren Yanqing , Sporn Michael B , Brinckerhoff Constance E 
Published: December 2008

Abstract
Introduction
We recently described the ability of retinoid X receptor (RXR) ligand LG100268 (LG268) to inhibit interleukin-1-beta (IL-1-β)-driven matrix metalloproteinase-1 (MMP-1) and MMP-13 gene expression in SW-1353 chondrosarcoma cells. Other investigators have demonstrated similar effects in chondrocytes treated with rosiglitazone, a ligand for peroxisome proliferator-activated receptor-gamma (PPARγ), for which RXR is an obligate dimerization partner. The goals of this study were to evaluate the inhibition of IL-1-β-induced expression of MMP-1 and MMP-13 by combinatorial treatment with RXR and PPARγ ligands and to investigate the molecular mechanisms of this inhibition.

Methods
We used real-time reverse transcription-polymerase chain reaction to measure LG268- and rosiglitazone-mediated inhibition of MMP gene transcription in IL-1-β-treated SW-1353 chondrosarcoma cells. An in vitro collagen destruction assay was a functional readout of MMP collagenolytic activity. Luciferase reporter assays tested the function of a putative regulatory element in the promoters of MMP-1 and MMP-13, and chromatin immunoprecipitation (ChIP) assays detected PPARγ and changes in histone acetylation at this site. Post-translational modification of RXR and PPARγ by small ubiquitin-like modifier (SUMO) was assayed with immunoprecipitation and Western blot.

Results
Rosiglitazone inhibited MMP-1 and MMP-13 expression in IL-1-β-treated SW-1353 cells at the mRNA and heterogeneous nuclear RNA levels and blunted IL-1-β-induced collagen destruction in vitro. Combining LG268 and rosiglitazone had an additive inhibitory effect on MMP-1 and MMP-13 transcription and collagenolysis. IL-1-β inhibited luciferase expression in the MMP reporter assay, but rosiglitazone and LG268 had no effect. ChIP indicated that treatment with IL-1-β, but not LG268 and rosiglitazone, increased PPARγ at the proximal promoters of both MMPs. Finally, rosiglitazone or LG268 induced 'cross-SUMOylation' of both the target receptor and its binding partner, and IL-1-β-alone had no effect on SUMOylation of RXR and PPARγ but antagonized the ligand-induced SUMOylation of both receptors.

Conclusions
The PPARγ and RXR ligands rosiglitazone and LG268 may act through similar mechanisms, inhibiting MMP-1 and MMP-13 transcription. Combinatorial treatment activates each partner of the RXR:PPARγ heterodimer and inhibits IL-1-β-induced expression of MMP-1 and MMP-13 more effectively than either compound alone. We conclude that the efficacy of combined treatment with lower doses of each drug may minimize potential side effects of treatment with these compounds.