bluuebunny/crossref_metadata_2025_split huggingface dataset:
Profile-specific survival estimates: Making reports of clinical trials more patient-relevant
Authors: Julien Marilyse , Hanley James A 
Published: March 2008

Background When considering treatment options, a physician needs to know the prognosis corresponding to the risk profile of the patient seeking treatment. Reports of clinical trials generally address treatment-specific survival probabilities only in the aggregate, i.e., for the typical patient, and often express the difference in survival as a hazard ratio. Such summaries do not provide treatment-specific survival probabilities (and thus the absolute difference in these probabilities) for patient profiles that are not near the typical of those in the trial. Despite the fact that Cox intended his hazard regression method to be used to produce such profile-specific survival estimates, and even showed how to calculate them, authors are either unaware that this is possible, or else choose not to report them. Purpose To illustrate how treatment- and profile-specific survival estimates are obtained from the Cox method, and can be displayed in a compact form. Methods We derive treatment- and profile-specific survival probabilities from the estimated survival function for the `reference' profile. Data from the Systolic Hypertension in the Elderly Program study serve as an illustration. Results Two different formats, tabular and nomogram-based, allow the entire set of estimated treatment- and profile-specific survival probabilities to be reported. Limitations Estimates are limited to the profiles within the covariate-space spanned by the trial, and depend on the correctness of the model. Conclusion Treatment- and profile-specific survival estimates are practice-relevant, almost never reported, estimable from the Cox model, and easy to report in a compact form. Clinical Trials 2008; 5: 107—115. http://ctj.sagepub.com
Meta-analysis of rare events: an update and sensitivity analysis of cardiovascular events in randomized trials of rosiglitazone
Authors: Dahabreh Issa J 
Published: March 2008

Background A meta-analysis of randomized controlled trials suggested that rosiglitazone, a drug used for the treatment of diabetes, may be associated with an increased risk of cardiovascular adverse events. Three large randomized trials, designed specifically to address cardiovascular outcomes of rosiglitazone treatment, have published new or updated results. Purpose To provide a cumulative summary of the clinical trial evidence on rosiglitazone along with a sensitivity analysis of different methods to estimate the combined effect. Methods A previous meta-analysis (N Engl J Med 2007; 356: 2457—2471) was updated to include event rates of myocardial infarction and death due to cardiovascular causes from the recent reports of the RECORD, DREAM and ADOPT trials. Odds ratios (OR) with their confidence intervals were calculated for all outcomes using the Mantel—Haenszel method with Robins—Breslow—Greenland variance estimation and a fixed effects model. Sensitivity analysis was performed, using different methods for estimating the combined effect and using different continuity corrections for studies with zero events in one or both arms. Results Rosiglitazone was associated with an increased risk of myocardial infarction (OR, 1.29; CI: 1.01—1.66; p = 0.05) but not death due to cardiovascular causes (OR, 1.12; CI: 0.80—1.55; p = 0.58). Pooled analysis of the ADOPT, RECORD, and DREAM trials did not reach statistical significance for either myocardial infarction (OR, 1.29; CI: 0.95—1.74; p = 0.12) or death due to cardiovascular causes (OR, 0.90; CI: 0.61—1.33; p = 0.67). Based on these three trials, rosiglitazone was associated with a clear increase in the risk of heart failure (OR, 2.17; CI: 1.49—3.17; p<0.0001). Despite minor discrepancies, different calculation methods demonstrated an increased risk of myocardial infarction for rosiglitazone treated patients. There was no evidence of an association between rosiglitazone and death due to cardiovascular causes regardless of the calculation method used. The increased risk of heart failure conferred by rosiglitazone treatment was consistently demonstrated across different calculation methods. Limitations Trials with short-term follow-up and trials not specifically designed to evaluate cardiovascular outcomes were included in this meta-analysis and patient-level data where not available. Conclusions Rosiglitazone appears to be associated with an increased risk of myocardial infarction and heart failure, but not death due to cardiovascular causes. When a meta-analysis of rare events is contemplated, a thorough sensitivity analysis using different methods to combine studies and an evaluation of different continuity corrections should be undertaken. When possible, an individual patient data meta-analysis should be performed, allowing time-to-event analysis and the identification of patient subgroups at an increased risk of adverse outcomes. Clinical Trials 2008; 5: 116—120. http://ctj.sagepub.com
Review: New perspectives in the treatment of idiopathic pulmonary fibrosis
Authors: Rogliani Paola , Mura Marco , Assunta Porretta Maria , Saltini Cesare 
Published: March 2008

Idiopathic pulmonary “brosis (IPF) is the most frequent idiopathic interstitial pneumonia with a prevalence ranging from 5 to 15 per 100,000 persons, and above 175 per 100,000 in the older population. IPF is a relentlessly progressive “brotic lung disorder leading to death within a median duration of 3 years.It was hypothesized in the 1970s that pulmonary “brosis initiates as an “alveolitis” progressing to interstitial “brosis with connective tissue deposition, derangement of the lung architecture and functional impairment.However, in vitro studies indicated that alveolar/bronchiolar injured epithelial cells can drive the “brotic process in the absence of macrophages and with minimal in”ammation. This, together with the inability of classic immunosuppressive therapy to cure IPF, generated new pathogenesis paradigms and intense research into the role of the lack or the excessive production of anti-“brotic or pro“brotic mediators, oxidant injury, exaggerated coagulation, thus leading to investigate new treatment strategies. Preliminary results of some of such trials have shown signi“cant reductions in lung function decline, disease exacerbation and mortality.
Arformoterol and salmeterol in the treatment of chronic obstructive pulmonary disease: A one year evaluation of safety and tolerance
Authors: Donohue J.F. , Hanania N.A. , Sciarappa K.A. , Goodwin E. , Grogan D.R. , Baumgartner R.A. , Hanrahan J.P. 
Published: March 2008

Introduction: Concerns have been raised regarding the safety of extended use of long-acting β2-agonists (LABAs). The safety of arformoterol (50 µg QD), and salmeterol (42 µg BID), was assessed over 12 months in subjects with COPD. The study also examined the occurrence of tolerance with these agents, i.e. whether improvement in airway function diminished or frequency of exacerbations increased with 12-months of use. Methods: Subjects with COPD (mean FEV1 1.2 L, ~41% predicted) were enrolled in the study and randomized to receive nebulized arformoterol 50 µg QD ( n = 528) or salmeterol 42 µg BID (MDI; n = 265) in a prospective, multicenter, open-label, 12-month trial. The frequency of adverse events, COPD exacerbations, and use of short-acting bronchodilator agents were assessed throughout the study period. Pulmonary function was also examined. Results: Among treated subjects, the frequency of adverse events was similar for those taking arformoterol (90.5%) and salmeterol (88.3%). Tremor was more frequent among subjects treated with arformoterol (13.4%) than those treated with salmeterol (1.1%). The frequency of COPD exacerbations did not increase over 12 months for arformoterol and salmeterol (weeks 0—13: 15.7% and 11.7%, respectively; weeks 39—52: 10.0% and 9.4%, respectively). Supplemental ipratropium bromide and rescue racemic albuterol use decreased for both groups by 0.8 to 1.5 actuations/day, decreases that remained stable throughout the 52-week study. Mean predose (trough) FEV1 improved for arformoterol and salmeterol at week 13 (7.1% ± 17.0 and 7.6% ± 17.8, respectively) and the improvement continued at week 52 (5.9% and 6.2%, respectively). Mean peak percent predicted postdose FEV1 over the course of the 52-week study declined by about 2% for both treatments, but throughout was higher for arformoterol than for salmeterol. Conclusion: In this trial, both arformoterol 50 µg QD and salmeterol 42 µg BID were well tolerated in patients with COPD. Both LABAs produced effective bronchodilation and their use was not associated with the development of clinically meaningful tolerance over a 1-year treatment period.
Arterio-venous access in end-stage renal disease patients and pulmonary hypertension
Authors: Yigla Mordechai , Banderski Regina , Azzam Zaher S. , Reisner Shimon A. , Nakhoul Farid 
Published: March 2008

Background: The syndrome of pulmonary hypertension (PHT) in end-stage renal disease (ESRD) has been described in patients on chronic hemodialysis (HD) therapy via arterial-venous (A-V) access. However, the exact timing for the development of the PHT is unknown. This study was designed to evaluate changes in pulmonary artery pressure (PAP) following creation of the vascular access. Patients and Methods: PAP and cardiac-output (CO) values were recorded in 12 pre-dialysis patients without PHT a few months after the access formation, before treatment with HD was started, and the prevalence of PHT was calculated. Clinical data was compared between patients with and without PHT. Results: The systolic PAP values were increased in “ve of the 12 pre-dialysis patients (42%) by 21±9 mm Hg to more than 35 mm Hg. Patients with and without PHT differed only in that CO was signi“cantly higher among the former. Conclusions: The development of PHT following access formation represents a failure of the pulmonary circulation to accommodate the access-mediated elevated CO. Pre-dialysis patients scheduled for access formation should be screened for the presence of sub-clinical PHT. “Positive” patients should proceed to peritoneal dialysis or advance to kidney transplantation; rather than getting access and HD therapy.
Understanding Why Adhesion in Extrusion Coating Decreases With Diminishing Coating Thickness
Authors: Morris Barry A. 
Published: March 2008

It is well known that in extrusion coating, the coating adhesion to the substrate decreases with decreasing thickness. The study on this phenomenon is divided into three parts. Part I explores the reduction in adhesion of LDPE to paper and other porous substrates. Several hypotheses are proposed for the origin of this decrease, including a reduction in oxidation time, faster cooling in the air gap, and more rapid quenching in the nip. A model of the molten polymer penetration into the substrate shows that the greatest effect is cooling in the nip; thinner coatings have less time to flow into the substrate interstices once the chill roll contact is made. The model results agree well with experimental adhesion data from the literature. In Part II, adhesion to aluminum foil and other nonporous substrates is studied. Several hypotheses are proposed for why peel strength decreases in these structures, including a reduction in the air gap time, faster air gap cooling, more rapid nip quenching, and stress imposed during drawing. Modeling and experimental results show that cooling in the nip and imposed stress have the greatest impact. In Part III, the peel test is analyzed to understand why the peel strength of better adhering adhesives are more sensitive to changes in coating thickness. The analysis shows that changes in the critical dimension of the deformation region at the peel front may be responsible.
Regulation of tumor necrosis factor receptor-1 and the IKK-NF-κB pathway by LDL receptor–related protein explains the antiinflammatory activity of this receptor
Authors: Gaultier Alban , Arandjelovic Sanja , Niessen Sherry , Overton Cheryl D. , Linton MacRae F. , Fazio Sergio , Campana W. Marie , Cravatt Benjamin F. , Gonias Steven L. 
Published: March 2008

AbstractLow-density lipoprotein receptor–related protein (LRP-1) functions in endocytosis and in cell signaling directly (by binding signaling adaptor proteins) or indirectly (by regulating levels of other cell-surface receptors). Because recent studies in rodents suggest that LRP-1 inhibits inflammation, we conducted activity-based protein profiling experiments to discover novel proteases, involved in inflammation, that are regulated by LRP-1. We found that activated complement proteases accumulate at increased levels when LRP-1 is absent. Although LRP-1 functions as an endocytic receptor for C1r and C1s, complement protease mRNA expression was increased in LRP-1–deficient cells, as was expression of inducible nitric oxide synthase (iNOS) and interleukin-6. Regulation of expression of inflammatory mediators was explained by the ability of LRP-1 to suppress basal cell signaling through the IκB kinase–nuclear factor-κB (NF-κB) pathway. LRP-1–deficient macrophages, isolated from mice, demonstrated increased expression of iNOS, C1r, and monocyte chemoattractant protein-1 (MCP-1); MCP-1 expression was inhibited by NF-κB antagonism. The mechanism by which LRP-1 inhibits NF-κB activity involves down-regulating cell-surface tumor necrosis factor receptor-1 (TNFR1) and thus, inhibition of autocrine TNFR1-initiated cell signaling. TNF-α–neutralizing antibody inhibited NF-κB activity selectively in LRP-1–deficient cells. We propose that LRP-1 suppresses expression of inflammatory mediators indirectly, by regulating TNFR1-dependent cell signaling through the IκB kinase–NF-κB pathway.
Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases
Authors: von Schantz Carina , Saharinen Juha , Kopra Outi , Cooper Jonathan D , Gentile Massimiliano , Hovatta Iiris , Peltonen Leena , Jalanko Anu 
Published: March 2008

Abstract

Background
The neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of the different forms of NCL suggest that common disease mechanisms may be involved. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln1 and Cln5. Both mouse-models replicate the NCL phenotype and neuropathology; the Cln1-/- model presents with early onset, severe neurodegenerative disease, whereas the Cln5-/- model produces a milder disease with a later onset.

Results
Here we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old Cln1-/- and Cln5-/- mice. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating neuronal growth cone stabilization display similar aberrations in both models. We analyzed locus specific gene expression and showed regional clustering of Cln1 and three major genes of this pathway, further supporting a close functional relationship between the corresponding gene products; adenylate cyclase-associated protein 1 (Cap1), protein tyrosine phosphatase receptor type F (Ptprf) and protein tyrosine phosphatase 4a2 (Ptp4a2). The evidence from the gene expression data, indicating changes in the growth cone assembly, was substantiated by the immunofluorescence staining patterns of Cln1-/- and Cln5-/- cortical neurons. These primary neurons displayed abnormalities in cytoskeleton-associated proteins actin and β-tubulin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3.

Conclusion
Our data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since CLN1 and CLN5 code for proteins with distinct functional roles these data may have implications for other forms of NCLs as well.
Role of TNF priming and adhesion molecules in neutrophil recruitment to intravascular immune complexes
Authors: Lauterbach Michael , O’Donnell Peter , Asano Kenichi , Mayadas Tanya N 
Published: March 2008

AbstractNeutrophils play an important role in immune complex (IC)-mediated diseases, but the mechanisms underlying their recruitment to sites of IC deposition remain largely undefined. Furthermore, neutrophils encounter cytokines that prime their effector functions, yet the physiological relevance of priming to neutrophil functions is unclear. Using intravital microscopy, we demonstrate that TNF treatment of neutrophils ex vivo significantly increased their adhesion in a model of intravascular ICs deposited in the cremaster muscle. Notably, TNF priming had no effect on neutrophil adhesion in the absence of ICs. Analyses of relevant knockout mice and neutrophil reconstitution revealed a critical role for FcγRs and the CD18 integrin Mac-1 in IC-mediated neutrophil adhesion. Furthermore, ICAM-1, a major Mac-1 ligand constitutively expressed on unactivated endothelium, significantly contributed to this process. These data suggest that TNF priming promotes FcγR interaction with intravascular ICs, leading to the binding of Mac-1 to ICAM-1 and subsequent neutrophil arrest.
Gr-1+CD11b+ cells as an accelerator of sepsis stemming fromPseudomonas aeruginosawound infection in thermally injured mice
Authors: Kobayashi Makiko , Yoshida Tsuyoshi , Takeuchi Dan , Jones Vickie C , Shigematsu Kenji , Herndon David N , Suzuki Fujio 
Published: March 2008

AbstractUsing a mouse model of thermal injury, we studied why antimicrobial peptides are not produced at the burn-site tissues and how this defect contributes to the increased susceptibility to Pseudomonas aeruginosa burn-wound infection. Logarithmic growth of P. aeruginosa was demonstrated locally (at the burn site) and systemically (in circulation) in thermally injured mice exposed to 102 CFU/mouse of the pathogen beneath the burn wound. However, neither systemic nor local growth of the pathogen was observed in sham burn mice when they were infected intradermally with 106 CFU/mouse P. aeruginosa. Murine β-defensins (MBDs) were detected in the skin homogenates of sham burn mice. However, the amounts of MBDs were reduced greatly in the same tissue homogenates from thermally injured mice. Gr-1+CD11b+ cells, with an ability to suppress antimicrobial peptide production by skin keratinocytes, were isolated from tissues surrounding the burn areas, and these cells were not obtained from skin tissues of sham burn mice. After intradermal inoculation of Gr-1+CD11b+ cells, which were isolated from burn-site tissues, the production of antimicrobial peptides around the cell-inoculation site of sham burn mice decreased. Also, like thermally injured mice, these mice were shown to be susceptible to P. aeruginosa intradermal infection. These results indicate that sepsis stemming from P. aeruginosa burn-wound infection is accelerated by burn-induced Gr-1+CD11b+ cells with abilities to suppress antimicrobial peptide production by epidermal keratinocytes.
S-phase entry leads to cell death in circulating T cells from HIV-infected persons
Authors: Sieg Scott F , Bazdar Douglas A , Lederman Michael M 
Published: March 2008

AbstractCentral memory T cells are thought to play a critical role in memory T cell homoestasis by undergoing self-renewal and by maturating into effector T cells that mediate immunity at tissue sites. Circulating T cells in S phase of the cell cycle are found at increased frequencies during HIV infection and are predominantly composed of cells with a central memory phenotype. Here, we tested the hypothesis that CD4 and CD8 S-phase T cells have different capacities to complete cell cycle and survive. S-phase T cells in peripheral blood from HIV-infected donors were identified by incubating whole blood with BrdU ex vivo. Upon in vitro cultivation, S-phase T cells were more likely to die than to complete mitotic division. Intrinsic differences were observed between CD4 and CD8 S-phase T cells during incubation. Higher frequencies of CD4+ S-phase T cell underwent apoptosis after incubation in medium alone or after TCR stimulation, and CD4+ S-phase T cells were less readily induced to proliferate after incubation with IL-2 than were CD8+ S-phase T cells. CD4+ and CD8+ S-phase T cells expressed low levels of Bcl-2, which could contribute to their heightened susceptibility to cell death. Intrinsic differences in the proliferation and survival of CD4+ and CD8+ S-phase T cells could influence the homeostatic maintenance of these T cell subsets in HIV disease.
Moraxella catarrhalis-dependent tonsillar B cell activation does not lead to apoptosis but to vigorous proliferation resulting in nonspecific IgM production
Authors: Jendholm Johan , Samuelsson Martin , Cardell Lars-Olaf , Forsgren Arne , Riesbeck Kristian 
Published: March 2008

AbstractThe respiratory pathogen Moraxella catarrhalis has a high affinity for human IgD and is mitogenic for peripheral blood B lymphocytes. Moraxella IgD-binding protein, which is a multifunctional outer membrane protein with adhesive properties, is responsible for the interaction. Previous experiments with the Ig-binding B cell superantigens protein A and protein L from Staphylococcus aureus and Peptostreptococcus magnus, respectively, have suggested that nonimmune BCR cross-linking induces B cell apoptosis through the intrinsic pathway. The goal of this study was to characterize early and late B cell events in the presence of M. catarrhalis in comparison with S. aureus. Despite an increased phosphatidyl serine translocation as revealed by Annexin V binding in flow cytometry analyses, neither M. catarrhalis nor S. aureus induced activation-associated apoptotic cell death in purified human tonsillar B cells. In contrast, a vigorous B cell proliferation, as quantified using thymidine incorporation and CFSE staining, was observed. An increased expression of an array of surface proteins (i.e., CD19, CD21, CD40, CD45, CD54, CD69, CD86, CD95, and HLA-DR) and IgM production was found upon activation with M. catarrhalis. In conclusion, M. catarrhalis-dependent B cell activation does not result in apoptosis but in cell division and nonspecific IgM synthesis, suggesting that the bacterial interaction with tonsillar B cells serves to redirect the early adaptive immune response.
Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow
Authors: Cooper Dianne , Norling Lucy V , Perretti Mauro 
Published: March 2008

AbstractGalectin-1 (Gal-1) is a β-galactoside-binding protein endowed with anti-inflammatory properties. The purpose of this study was to investigate the effects of endogenous and exogenous Gal-1 on neutrophil recruitment onto TNF-treated endothelium. The effect of human recombinant (hr)Gal-1 on markers of neutrophil activation (CD11b expression, P-selectin glycoprotein ligand 1, and L-selectin shedding) was also assessed. Gal-1 inhibited the platelet-activating factor-induced increase in CD11b expression in a concentration-dependent manner, as assessed by flow cytometry. To determine the effects of Gal-1 on neutrophil recruitment, an in vitro flow chamber was used: Preincubation of neutrophils with hrGal-1 significantly decreased the extent of capture, rolling, and adhesion on activated endothelial monolayers. This inhibition was shared with the endogenous protein, as knockdown of endothelial Gal-1 using small interfering RNA resulted in a significant increase in the number of cells captured and rolling. To verify the effects of Gal-1 in an in vivo system, intravital microscopy of Gal-1 null mice and their wild-type counterparts was performed. Leukocyte adhesion and emigration were increased significantly in the cremasteric circulation of Gal-1 null mice inflamed with IL-1β. These findings indicate that Gal-1 functions to limit neutrophil recruitment onto a TNF-treated endothelium, a property that may underline its inhibitory effects in acute inflammation.