bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension
Authors: Schermuly R. T. , Stasch J-P. , Pullamsetti S. S. , Middendorff R. , Müller D. , Schlüter K-D. , Dingendorf A. , Hackemack S. , Kolosionek E. , Kaulen C. , Dumitrascu R. , Weissmann N. , Mittendorf J. , Klepetko W. , Seeger W. , Ghofrani H. A. , Grimminger F. 
Published: June 2008

Alterations of the nitric oxide receptor, soluble guanylate cyclase (sGC) may contribute to the pathophysiology of pulmonary arterial hypertension (PAH). In the present study, the expression of sGC in explanted lung tissue of PAH patients was studied and the effects of the sGC stimulator BAY 63-2521 on enzyme activity, and haemodynamics and vascular remodelling were investigated in two independent animal models of PAH.Strong upregulation of sGC in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was demonstrated by immunohistochemistry. Upregulation of sGC was detected, similarly to humans, in the structurally remodelled smooth muscle layer in chronic hypoxic mouse lungs and lungs from monocrotaline (MCT)-injected rats. BAY 63-2521 is a novel, orally available compound that directly stimulates sGC and sensitises it to its physiological stimulator, nitric oxide. Chronic treatment of hypoxic mice and MCT-injected rats, with fully established PAH, with BAY 63-2521 (10 mg·kg−1·day−1) partially reversed the PAH, the right heart hypertrophy and the structural remodelling of the lung vasculature.Upregulation of soluble guanylate cyclase in pulmonary arterial smooth muscle cells was noted in human idiopathic pulmonary arterial hypertension lungs and lungs from animal models of pulmonary arterial hypertension. Stimulation of soluble guanylate cyclase reversed right heart hypertrophy and structural lung vascular remodelling. Soluble guanylate cyclase may thus offer a new target for therapeutic intervention in pulmonary arterial hypertension.
Collapsibility of the relaxed pharynx and risk of sleep apnoea
Authors: Oliven A. , Aspandiarov E. , Gankin I. , Gaitini L. , Tov N. 
Published: June 2008

The present study measured hypotonic pharyngeal collapsibility in subjects not known to have obstructive sleep apnoea (OSA), and assessed the variables that affect collapsibility and the relationship with OSA.The critical value of positive end-expiratory pressure (Pcrit) was measured under the hypotonic condition of anaesthesia in 227 subjects who underwent elective surgery. The risk of OSA in this population was estimated using the Berlin questionnaire.The meanPcritfor all subjects was positive (above atmospheric), ranging from 0.69 (95% confidence interval (CI) -7.39–8.77) to 4.0 (CI -4.82–12.82) cmH2O for subjects with low and high prevalence of OSA, respectively.Pcrit≤-5 cmH2O was only found in 3.1% of the study subjects. In the general population,Pcritwas similar in males and females and correlated positively with increasing age, while a correlation with neck circumference was found only in males.Pcritaccounted for only 12.25% of the variability in OSA risk score.In conclusion, subjects with high critical value of positive end-expiratory pressure are at an increased risk for developing obstructive sleep apnoea. However, the human pharynx is prone to collapse and occludes in most people in the absence of neuromuscular support. Therefore, in most subjects, the level of neuromuscular activity may ultimately determine the occurrence of sleep apnoea.
Effects of hyperinflation on the oxygen pulse as a marker of cardiac performance in COPD
Authors: Vassaux C. , Torre-Bouscoulet L. , Zeineldine S. , Cortopassi F. , Paz-Díaz H. , Celli B. R. , Pinto-Plata V. M. 
Published: June 2008

A decreased inspiratory capacity (IC)/total lung capacity (TLC) ratio is associated with dynamic hyperinflation and decreased exercise capacity. The present authors hypothesised that static (low IC/TLC) and dynamic hyperinflation impair cardiac function as assessed by oxygen pulse at rest and during cardiopulmonary exercise testing (CPET).Lung function, body mass index, hand grip strength and CPET parameters were measured (oxygen uptake (mL·kg−1·min−1) and oxygen pulse (mL·beat−1)) in 87 chronic obstructive pulmonary disease (COPD) patients (American Thoracic Society/European Respiratory Society/Global Initiative for Chronic Obstructive Lung Disease stage 3–4) and 46 controls. The patients were divided into those with IC/TLC >25% or ≤25%.The IC/TLC ratio at rest and at peak exercise was associated significantly with oxygen pulse. Patients with IC/TLC ≤25% (n = 45) had significantly lower exercise capacity, peak oxygen pulse, peak minus baseline oxygen pulse, peak IC, peak IC/TLC ratio and % change from baseline to peak IC/TLC ratio compared with patients with IC/TLC >25% and controls. During CPET, the oxygen pulse was lower at iso-work in patients with IC/TLC ≤25% than in those with IC/TLC >25%.Resting hyperinflation (inspiratory capacity/total lung capacity) is associated with lower oxygen pulse, peak exercise inspiratory capacity/total lung capacity and exercise capacity in patients with severe chronic obstructive pulmonary disease. The present results support an interaction between hyperinflation and decreased cardiac function that may contribute to exercise limitation in these patients.
Adherence to guidelines’ empirical antibiotic recommendations and community-acquired pneumonia outcome
Authors: Dambrava P. G. , Torres A. , Vallès X. , Mensa J. , Marcos M. A. , Peñarroja G. , Camps M. , Estruch R. , Sánchez M. , Menéndez R. , Niederman M. S. 
Published: June 2008

The American Thoracic Society (ATS) published guidelines for the treatment and management of community-acquired pneumonia in 2001, but the impact of adherence on outcomes such as mortality and length of stay is not well defined.A study of 780 patients with community-acquired pneumonia consecutively admitted to hospital over 1 yr was carried out. Nursing home patients were excluded.Overall adherence to antibiotics recommended in the ATS guidelines was 84%. The lowest adherence was found in patients admitted to an intensive care unit (52%), especially those at risk of infection withPseudomonas aeruginosa(ATS group IVb). However, very few patients from this group were indeed infected withP. aeruginosa. This could be explained by the exclusion of the nursing home patients. There was a difference in mortality between patients that received adherent and nonadherent regimens (3versus10.6%). There was a difference in length of stay between patients receiving adherent and nonadherent regimens (7.6versus10.4 days). This result was confirmed on multivariate analysis.Adherence to the 2001 American Thoracic Society guidelines was high except in community-acquired pneumonia patients admitted to an intensive care unit. Length of stay was shorter in patients who received adherent rather than nonadherent antibiotic regimens.
Current clinical guideline definitions of airflow obstruction and COPD overdiagnosis in primary care
Authors: Schermer T. R. J. , Smeele I. J. M. , Thoonen B. P. A. , Lucas A. E. M. , Grootens J. G. , van Boxem T. J. , Heijdra Y. F. , van Weel C. 
Published: June 2008

The aim of the present study was to establish the agreement between two recommended definitions of airflow obstruction in symptomatic adults referred for spirometry by their general practitioner, and investigate how rates of airflow obstruction change when pre-bronchodilator instead of post-bronchodilator spirometry is performed.The diagnostic spirometric results of 14,056 adults with respiratory obstruction were analysed. Differences in interpretation between a fixed 0.70 forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) cut-off point and a sex- and age-specific lower limit of normal cut-off point for this ratio were investigated.Of the subjects, 53% were female and 69% were current or ex-smokers. The mean post-bronchodilator FEV1/FVC was 0.73 in males and 0.78 in females. The sensitivity of the fixed relative to the lower limit of normal cut-off point definition was 97.9%, with a specificity of 91.2%, positive predictive value of 72.0% and negative predictive value of 99.5%. For the subgroup of current or ex-smokers aged ≥50 yrs, these values were 100, 82.0, 69.2 and 100%, respectively. The proportion of false positive diagnoses using the fixed cut-off point increased with age. The positive predictive value of pre-bronchodilator airflow obstruction was 74.7% among current or ex-smokers aged ≥50 yrs.The current clinical guideline-recommended fixed 0.70 forced expiratory volume in one second/forced vital capacity cut-off point leads to substantial overdiagnosis of obstruction in middle-aged and elderly patients in primary care. Using pre-bronchodilator spirometry leads to a high rate of false positive interpretations of obstruction in primary care.
Sources of variation in baseline gene expression levels from toxicogenomics study control animals across multiple laboratories
Authors: Boedigheimer Michael J , Wolfinger Russell D , Bass Michael B , Bushel Pierre R , Chou Jeff W , Cooper Matthew , Corton J Christopher , Fostel Jennifer , Hester Susan , Lee Janice S , Liu Fenglong , Liu Jie , Qian Hui-Rong , Quackenbush John , Pettit Syril , Thompson Karol L 
Published: June 2008

Abstract

Background
The use of gene expression profiling in both clinical and laboratory settings would be enhanced by better characterization of variance due to individual, environmental, and technical factors. Meta-analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies could yield useful information on baseline fluctuations in gene expression, although control animal data has not been available on a scale and in a form best served for data-mining.

Results
A dataset of control animal microarray expression data was assembled by a working group of the Health and Environmental Sciences Institute's Technical Committee on the Application of Genomics in Mechanism Based Risk Assessment in order to provide a public resource for assessments of variability in baseline gene expression. Data from over 500 Affymetrix microarrays from control rat liver and kidney were collected from 16 different institutions. Thirty-five biological and technical factors were obtained for each animal, describing a wide range of study characteristics, and a subset were evaluated in detail for their contribution to total variability using multivariate statistical and graphical techniques.

Conclusion
The study factors that emerged as key sources of variability included gender, organ section, strain, and fasting state. These and other study factors were identified as key descriptors that should be included in the minimal information about a toxicogenomics study needed for interpretation of results by an independent source. Genes that are the most and least variable, gender-selective, or altered by fasting were also identified and functionally categorized. Better characterization of gene expression variability in control animals will aid in the design of toxicogenomics studies and in the interpretation of their results.
Sequencing and expression of two arsenic resistance operons with different functions in the highly arsenic-resistant strain Ochrobactrum tritici SCII24T
Authors: Branco Rita , Chung Ana-Paula , Morais Paula V 
Published: June 2008

Abstract

Background
Arsenic (As) is a natural metalloid, widely used in anthropogenic activities, that can exist in different oxidation states. Throughout the world, there are several environments contaminated with high amounts of arsenic where many organisms can survive. The most stable arsenical species are arsenate and arsenite that can be subject to chemically and microbiologically oxidation, reduction and methylation reactions. Organisms surviving in arsenic contaminated environments can have a diversity of mechanisms to resist to the harmful effects of arsenical compounds.

Results
The highly metal resistant Ochrobactrum tritici SCII24 was able to grow in media with arsenite (50 mM), arsenate (up to 200 mM) and antimonite (10 mM). This strain contains two arsenic and antimony resistance operons (ars 1 and ars 2), which were cloned and sequenced. Sequence analysis indicated that ars 1 operon contains five genes encoding the following proteins: ArsR, ArsD, ArsA, CBS-domain-containing protein and ArsB. The ars 2 operon is composed of six genes that encode two other ArsR, two ArsC (belonging to different families of arsenate reductases), one ACR3 and one ArsH-like protein. The involvement of ars operons in arsenic resistance was confirmed by cloning both of them in an Escherichia coli ars-mutant. The ars 1 operon conferred resistance to arsenite and antimonite on E. coli cells, whereas the ars 2 operon was also responsible for resistance to arsenite and arsenate. Although arsH was not required for arsenate resistance, this gene seems to be important to confer high levels of arsenite resistance. None of ars 1 genes were detected in the other type strains of genus Ochrobactrum, but sequences homologous with ars 2 operon were identified in some strains.

Conclusion
A new strategy for bacterial arsenic resistance is described in this work. Two operons involved in arsenic resistance, one giving resistance to arsenite and antimonite and the other giving resistance to arsenate were found in the same bacterial strain.
Development of multiple strain competitive index assays for Listeria monocytogenes using pIMC; a new site-specific integrative vector
Authors: Monk Ian R , Casey Pat G , Cronin Michael , Gahan Cormac GM , Hill Colin 
Published: June 2008

AbstractBackgroundThe foodborne, gram-positive pathogen,Listeria monocytogenes, is capable of causing lethal infections in compromised individuals. In the post genomic era ofL. monocytogenesresearch, techniques are required to identify and validate genes involved in the pathogenicity and environmental biology of the organism. The aim here was to develop a widely applicable method to tagL. monocytogenesstrains, with a particular emphasis on the development of multiple strain competitive index assays.ResultsWe have constructed a new site-specific integrative vector, pIMC, based on pPL2, for the selection ofL. monocytogenesfrom complex samples. The pIMC vector was further modified through the incorporation of IPTG inducible markers (antibiotic and phenotypic) to produce a suite of four vectors which allowed the discrimination of multiple strains from a single sample. We were able to perform murine infection studies with up to four EGDe isolates within a single mouse and showed that the tags did not impact upon growth rate or virulence. The system also allowed the identification of subtle differences in virulence between strains ofL. monocytogenescommonly used in laboratory studies.ConclusionThis study has developed a competitive index assay that can be broadly applied to allL. monocytogenesstrains. Improved statistical robustness of the data was observed, resulting in fewer mice being required for virulence assays. The competitive index assays provide a powerful method to analyse the virulence or fitness ofL. monocytogenesin complex biological samples.
Choline-stabilized orthosilicic acid supplementation as an adjunct to Calcium/Vitamin D3 stimulates markers of bone formation in osteopenic females: a randomized, placebo-controlled trial
Authors: Spector Tim D , Calomme Mario R , Anderson Simon H , Clement Gail , Bevan Liisa , Demeester Nathalie , Swaminathan Rami , Jugdaohsingh Ravin , Berghe Dirk A Vanden , Powell Jonathan J 
Published: June 2008

Abstract

Background
Mounting evidence supports a physiological role for silicon (Si) as orthosilicic acid (OSA, Si(OH)4) in bone formation. The effect of oral choline-stabilized orthosilicic acid (ch-OSA) on markers of bone turnover and bone mineral density (BMD) was investigated in a double-blind placebo-controlled trial.

Methods
Over 12-months, 136 women out of 184 randomized (T-score spine < -1.5) completed the study and received, daily, 1000 mg Ca and 20 μg cholecalciferol (Vit D3) and three different ch-OSA doses (3, 6 and 12 mg Si) or placebo. Bone formation markers in serum and urinary resorption markers were measured at baseline, and after 6 and 12 months. Femoral and lumbar BMD were measured at baseline and after 12 months by DEXA.

Results
Overall, there was a trend for ch-OSA to confer some additional benefit to Ca and Vit D3 treatment, especially for markers of bone formation, but only the marker for type I collagen formation (PINP) was significant at 12 months for the 6 and 12 mg Si dose (vs. placebo) without a clear dose response effect. A trend for a dose-corresponding increase was observed in the bone resorption marker, collagen type I C-terminal telopeptide (CTX-I).
Lumbar spine BMD did not change significantly. Post-hoc subgroup analysis (baseline T-score femur < -1) however was significant for the 6 mg dose at the femoral neck (T-test). There were no ch-OSA related adverse events observed and biochemical safety parameters remained within the normal range.

Conclusion
Combined therapy of ch-OSA and Ca/Vit D3 had a potential beneficial effect on bone collagen compared to Ca/Vit D3 alone which suggests that this treatment is of potential use in osteoporosis. NTR 1029
Safety and tolerability of combination antimalarial therapies for uncomplicated falciparum malaria in Ugandan children
Authors: Maiteki-Sebuguzi Catherine , Jagannathan Prasanna , Yau Vincent M , Clark Tamara D , Njama-Meya Denise , Nzarubara Bridget , Talisuna Ambrose O , Kamya Moses R , Rosenthal Philip J , Dorsey Grant , Staedke Sarah G 
Published: June 2008

Abstract

Background
Combination antimalarial therapy is recommended for the treatment of uncomplicated falciparum malaria in Africa; however, some concerns about the safety and tolerability of new regimens remain. This study compared the safety and tolerability of three combination antimalarial regimens in a cohort of Ugandan children.

Methods
A longitudinal, single-blind, randomized clinical trial of children was conducted between November 2004 and May 2007 in Kampala, Uganda. Upon diagnosis of the first episode of uncomplicated malaria, participants were randomized to treatment with amodiaquine + sulphadoxine-pyrimethamine (AQ+SP), artesunate + amodiaquine (AS+AQ), or artemether-lumefantrine (AL). Once randomized, participants received the same regimen for all subsequent episodes of uncomplicated malaria. Participants were actively monitored for adverse events for the first 14 days after each treatment, and then passively followed until their next study medication treatment, or withdrawal from study. Outcome measures included the risk of adverse events at 14 and 42 days after treatment.

Results
Of 601 enrolled children, 382 were diagnosed with at least one episode of uncomplicated malaria and were treated with study medications. The median age at treatment was 6.3 years (range 1.1 – 12.3 years). At 14 days of follow-up, AQ+SP treatment was associated with a higher risk of anorexia, weakness, and subjective fever than treatment with AL, and a higher risk of weakness, and subjective fever than treatment with AS+AQ. Treatment with AL was associated with a higher risk of elevated temperature. Repeated episodes of neutropaenia associated with AS+AQ were detected in one participant. Considering only children less than five years, those who received AQ+SP were at higher risk of developing moderate or severe anorexia and weakness than those treated with AL (anorexia: RR 3.82, 95% CI 1.59 – 9.17; weakness: RR 5.40, 95% CI 1.86 – 15.7), or AS+AQ (anorexia: RR 2.10, 95% CI 1.04 – 4.23; weakness: RR 2.26, 95% CI 1.01 – 5.05). Extending the analysis to 42 days of follow-up had little impact on the findings.

Conclusion
This study confirms the safety and tolerability of AS+AQ and AL in Ugandan children, and suggests that AQ+SP is safe, but less well-tolerated, particularly in younger children. As newer antimalarial regimens are deployed, collecting data on their safety and tolerability will be essential.

Trial registration
Current Controlled Trials Identifier ISRCTN37517549
Molecular profiling of angiogenesis in hypericin mediated photodynamic therapy
Authors: Bhuvaneswari Ramaswamy , Gan Yik Y , Lucky Sasidharan S , Chin William WL , Ali Seyed M , Soo Khee C , Olivo Malini 
Published: June 2008

Abstract

Background
Photodynamic therapy (PDT) involves the administration of a tumor-localizing photosensitizing drug, which is activated by light of specific wavelength in the presence of molecular oxygen thus generating reactive oxygen species that is toxic to the tumor cells. PDT selectively destroys photosensitized tissue leading to various cellular and molecular responses. The present study was designed to examine the angiogenic responses at short (0.5 h) and long (6 h) drug light interval (DLI) hypericin-PDT (HY-PDT) treatment at 24 h and 30 days post treatment in a human bladder carcinoma xenograft model. As short DLI targets tumor vasculature and longer DLI induces greater cellular damage, we hypothesized a differential effect of these treatments on the expression of angiogenic factors.

Results
Immunohistochemistry (IHC) results showed minimal CD31 stained endothelium at 24 h post short DLI PDT indicating extensive vascular damage. Angiogenic proteins such as vascular endothelial growth factor (VEGF), tumor necrosis growth factor-α (TNF-α), interferon-α (IFN-α) and basic fibroblast growth factor (bFGF) were expressed to a greater extent in cellular targeting long DLI PDT compared to vascular mediated short DLI PDT. Gene expression profiling for angiogenesis pathway demonstrated downregulation of adhesion molecules – cadherin 5, collagen alpha 1 and 3 at 24 h post treatment. Hepatocyte growth factor (HGF) and Ephrin-A3 (EFNA3) were upregulated in all treatment groups suggesting a possible activation of c-Met and Ephrin-Eph signaling pathways.

Conclusion
In conclusion, long DLI HY-PDT induces upregulation of angiogenic proteins. Differential expression of genes involved in the angiogenesis pathway was observed in the various groups treated with HY-PDT.
Bioavailable constituents/metabolites of pomegranate (Punica granatum L) preferentially inhibit COX2 activity ex vivo and IL-1beta-induced PGE2 production in human chondrocytes i n vitro
Authors: Shukla Meenakshi , Gupta Kalpana , Rasheed Zafar , Khan Khursheed A , Haqqi Tariq M 
Published: June 2008

Abstract
Several recent studies have documented that supplementation with pomegranate fruit extract inhibits inflammatory symptoms in vivo. However, the molecular basis of the observed effects has not been fully revealed. Although previous studies have documented the inhibition of nitric oxide and cyclooxygenase (COX) activity in vitro by plant and fruit extracts added directly into the culture medium but whether concentrations of bioactive compounds sufficient enough to exert such inhibitory effects in vivo can be achieved through oral consumption has not been reported. In the present study we determined the effect of rabbit plasma obtained after ingestion of a polyphenol rich extract of pomegranate fruit (PFE) on COX enzyme activity ex vivo and the IL-1β-induced production of NO and PGE2 in chondrocytes in vitro. Plasma samples collected before and 2 hr after supplementation with PFE were tested. Plasma samples collected after oral ingestion of PFE were found to inhibit the IL-1β-induced PGE2 and NO production in chondrocytes. These same plasma samples also inhibited both COX-1 and COX-2 enzyme activity ex vivo but the effect was more pronounced on the enzyme activity of COX-2 enzyme. Taken together these results provide additional evidence of the bioavailability and bioactivity of compounds present in pomegranate fruit after oral ingestion. Furthermore, these studies suggest that PFE-derived bioavailable compounds may exert an anti-inflammatory effect by inhibiting the inflammatory cytokine-induced production of PGE2 and NO in vivo.