bluuebunny/crossref_metadata_2025 huggingface dataset:
A predictive probability design for phase II cancer clinical trials
Authors: Lee J Jack , Liu Diane D
Published: March 2008

Background Two- or three-stage designs are commonly used in phase II cancer clinical trials. These designs possess good frequentist properties and allow early termination of the trial when the interim data indicate that the experimental regimen is inefficacious. The rigid study design, however, can be difficult to follow exactly because the response has to be evaluated at prespecified fixed number of patients.

Purpose Our goal is to develop an efficient and flexible design that possesses desirable statistical properties.

Methods A flexible design based on Bayesian predictive probability and the minimax criterion is constructed. A three-dimensional search algorithm is implemented to determine the design parameters.

Results The new design controls type I and type II error rates, and allows continuous monitoring of the trial outcome. Consequently, under the null hypothesis when the experimental treatment is not efficacious, the design is more efficient in stopping the trial earlier, which results in a smaller expected sample size. Exact computation and simulation studies demonstrate that the predictive probability design possesses good operating characteristics.

Limitations The predictive probability design is more computationally intensive than two- or three-stage designs. Similar to all designs with early stopping due to futility, the resulting estimate of treatment efficacy may be biased.

Conclusions The predictive probability design is efficient and remains robust in controlling type I and type II error rates when the trial conduct deviates from the original design. It is more adaptable than traditional multi-stage designs in evaluating the study outcome, hence, it is easier to implement. S-PLUS/R programs are provided to assist the study design. Clinical Trials 2008; 5: 93—106. http://ctj.sagepub.com
Implementation of NIH inclusion guidelines: survey of NIH study section members
Authors: Taylor Holly A
Published: March 2008

Background Current National Institutes of Health (NIH) policy mandates the inclusion of women, minorities and children in clinical research. Institutional Review Boards (IRB), NIH Scientific Review Groups (SRG) and NIH program staff all have responsibility for the evaluation of Principal Investigator (PI) adherence to the inclusion guidelines.

Purpose The purpose of this survey was to describe the experience with and attitudes of SRG members toward the inclusion guidelines and to identify characteristics of respondents that predict their attitudes towards the policy. Methods A survey was sent to 746 SRG members. 425 SRG members responded and univariate and bivariate statistical analysis conducted.

Results The results of the survey identify one clear measure of success regarding the implementation of the NIH guidelines; SRG members indicate the guidelines are in part responsible for their attention to the inclusion of women, minorities and children in clinical research. In addition, SRG members believe that gender and race are important factors when assessing the diversity of study samples and that the current NIH guidelines are adequate for encouraging their inclusion. As a proxy measure of success, SRG members believe that PIs responsible for protocols reviewed by their study group are generally compliant with the inclusion guidelines. Limitation At least one potential limitation of this study is that while an effort was made to assure confidentiality, because the project was funded by the NIH, respondents may have been less critical of the guidelines than they would have been if the study was funded by non-NIH funds.

Conclusion Future research ought to explore whether IRB members and NIH program officers find PIs to be compliant as their projects get underway. In addition, more research ought to be conducted to assess the downstream effects of this important social policy. Clinical Trials 2008; 5: 140—146. http://ctj.sagepub.com
Long-term drug prevention trials
Authors: Meinert Curtis L
Published: March 2008

A randomized trial is a randomized trial. The basic ingredients do not change with different purposes whether for treatment or prevention of disease. Likewise, the problems and difficulties are mostly the same. But there are differences in approach and philosophy depending on whether for treatment or prevention of disease. One thing setting prevention trials apart from treatment trials is the risk-benefit calculus of the two classes of trials. Treatment trials are undertaken to `cure' or ameliorate disease, whereas, prevention trials are undertaken in the hope of preventing or delaying onset of disease. The risks of harm in treatment trials is contemporaneous with prospects for benefit making the calculus reasonably straightforward. But that time relationship does not exist in long-term drug prevention trials where the risks from treatment start accruing on initiation of treatment, but where the prospect of benefit is down the road and comes, if all, in the form of disease avoided. This separation of risk versus benefit makes for difficult decisions as to how long to continue a trial in the absence of a difference in the test-assigned versus the control-assigned group. Other differences relate to choice of study treatments, choice of outcome measure, approach to recruitment and age cutoffs, and issues related to monitoring. Clinical Trials 2008; 5: 168—176. http:// ctj.sagepub.com
Maintaining confidentiality of interim data to enhance trial integrity and credibility
Authors: Fleming Thomas R , Sharples Katrina , McCall John , Moore Andrew , Rodgers Anthony , Stewart Ralph
Published: March 2008

Background For clinical trials of interventions that could affect mortality or major morbidity, Data Monitoring Committees have an important role in safeguarding patient interests and enhancing trial integrity and credibility. In trials overseen by an independent DMC it is widely recognized that interim data should remain confidential to the DMC and to the statistical group preparing reports. However, we have found that the principle of confidentiality is not always followed in practice, particularly where the interim data include complete results on a short-term outcome measure.

Purpose To discuss the reasoning and evidence supporting the principle of confidentiality of interim data with emphasis on the setting where the interim data include complete results on a short-term outcome.

Methods We review the reasons why wider access to interim data can increase the risk of false positive or false negative conclusions and discuss the types of harm which can occur. We provide illustrations and insights from recent experiences and discuss the level of consensus in the research community.

Results The arguments in favor of early release of interim data include the need to provide reliable data in a timely manner to patients and physicians, the potential to increase the enthusiasm of trial investigators, and to restore equipoise. However interim data, even where these include complete results on a short-term outcome measure, provide an unreliable and biased assessment of the overall benefit-to-risk profile of the trial treatments. Pre-judgment based on over-interpretation of such interim data can affect recruitment, treatment delivery, and follow-up, risking the ability of the trial to achieve its goals.

Conclusions In order to preserve the integrity of a trial and safeguard the interests of patients, interim data, including complete data on short-term outcomes, should remain confidential to the DMC and the statistical group responsible for preparing interim reports until the trial has achieved its primary objectives. Clinical Trials 2008; 5: 157—167. http://ctj.sagepub.com
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
Evaluating the safety of a rotavirus vaccine: the REST of the story
Authors: Heyse Joseph F , Kuter Barbara J , Dallas Michael J , Heaton Penny
Published: March 2008

The Rotavirus Efficacy and Safety Trial (REST) was a blinded, placebo-controlled study of the live pentavalent human-bovine vaccine, RotaTeq® (Merck & Co. Inc., West Point, PA). REST was noteworthy because its primary objective was to evaluate the safety of RotaTeq® with regard to intussusception, a rare intestinal illness that occurs with a background incidence of approximately 50 cases per 100 000 infant years. The study involved approximately 70 000 infants at over 500 study sites in 11 countries. The study demonstrated that the risk of intussusception was similar in vaccine and placebo recipients and that the vaccine prevented rotavirus gastroenteritis, ameliorated the severity of disease in those who had any disease, and substantially reduced rotavirus-associated hospitalizations and other health care contacts. This report provides an in-depth review of the background, statistical and regulatory considerations, and execution of REST. We describe the rationale and methods used for sample size, continuous safety monitoring, group sequential design, and detailed study execution. The results of the study have been reported elsewhere. The design and conduct of this study may serve as a useful model for planning other future large-scale clinical trials, especially those evaluating uncommon adverse events. Clinical Trials 2008; 5: 131—139. http:// ctj.sagepub.com
Where to from here?
Authors: Davis Glyn
Published: March 2008

Australian public universities are hybrid public—private institutions. Though established and regulated by government, they have always enjoyed substantial academic autonomy and for most of their history raised some of their revenue privately. Both these aspects have become more marked over the last twenty years, with increased regulation of publicly supported activities coinciding with greater reliance on highly competitive markets for income. Though Australian public universities face major difficulties, combining public and private in the same institution has avoided the two-tier system found in Australian schools and hospitals, and encouraged universities to become more responsive to students
Reforming systems and institutions of higher learning
Authors: Jařab Josef
Published: March 2008

Before Europe — as a continent — could seriously think of creating a common European Higher Education Area grave differences between the former West and East had to be dealt with. The fall of the Iron Curtain in 1989 made it possible to start reforming totalitarian educational systems and introduce principles of democratization and academic liberties. The transition period was not an easy one but neither did the process of harmonization and integration of higher learning in the freer part of the continent proceed without hindrances. The drafting and signing of the Bologna Magna Charta Universitatum, the declaration and launching of the Bologna Process, the activities and resolutions of the Council of Europe, UNESCO, the OECD and the European Union have proved decisive catalyzers in the process, which has progressed considerably, but has still to face some challenges before it achieves its full potential and a functional common higher education area in Europe and in the global context is created.
A new synergy for universities
Authors: Gaffikin Frank , Morrissey Mike
Published: March 2008

UK universities currently face three main challenges, related to the linked factors of development, deficit and duty. This article focuses on the final feature in the context of the former two. Specifically, it addresses the potential and problems associated with university—community partnerships, distinguishing between concepts of 'outreach' and 'engagement' that have dominated the US experience of such an interface. Through a case study analysis of the University of Ulster's Springvale project, it explores a model for effective partnership between the community and tertiary education sectors in contemporary society.
Governing the governors
Authors: Carlen Pat
Published: March 2008

This article analyses the governmental context within which governors of English women's prisons were struggling to implement the vision of the new Women's Policy Group and comply with the mass of new `regulations' for the governance of women's prisons at the beginning of the 20th century.
The socio-legal dynamics and implications of `diversion'
Authors: Fischer Benedikt , Wortley Scot , Webster Cheryl , Kirst Maritt
Published: March 2008

This article explores the socio-legal dynamics and implications of the `John School' diversion programme for prostitution offenders in Toronto, Canada. The analysis is based on quantitative and qualitative data collected as part of an evaluation study of the programme conducted between 1999 and 2001. The analysis begins by exploring the socio-political forces that have shaped prostitution control in Canada over the last century and ultimately led to the emergence of the `John School' as a reform compromise. The article subsequently investigates the particular role of `victims' discourses within the rationale and practices of the `John School' initiative. It traces the ambiguous nature of the programme's objectives by contrasting its widely promoted `educational' and `constructive' aims with the more punitive qualities that emerge in practice. Drawing from the critical literature on informal justice and diversion, it is evidenced that the programme focuses disproportionately on participants from lower socio-economic classes. Serious questions are also raised with regards to `due process'. Particular attention is given to the requirement by participants to waive basic procedural rights in return for admission in the `John School' programme and the subsequent withdrawal of criminal charges. The degree of `choice' involved in accepting these conditions is evaluated with regard to the specific characteristics of the target population. Policy implications are discussed.
Review: Surfactant protein D: A lung specific biomarker in COPD?
Authors: Sin Don D. , Pahlavan Payam S. , Man S.F. Paul
Published: March 2008

A major impediment in the development of novel drugs for chronic obstructive pulmonary disease (COPD) has been the scarcity of a well-validated, robust, and easily obtainable intermediate end point such as serum biomarkers. To date the best serum biomarkers in COPD have been non-speci“c pro-in”ammatory molecules synthesized largely by extra-pulmonary organs. In COPD, an ideal biomarker would be one that (1) was produced mostly in the lungs (and was reliably measurable in the peripheral circulation using commercially available kits), (2) changed with the clinical status of patients or with relevant exposures; and (3) had inherent functional attributes that suggested a possible causal role in the pathogenesis of the disease. In this paper, we review one promising systemic biomarker that ful“lls some of these criteria, surfactant protein D (SPD).
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.
Review: Gender differences following percutaneous coronary intervention
Authors: Holmvang Lene , Mickley Hans
Published: March 2008

PCI is effective for reducing symptoms in patients with stable angina pectoris but does not improve prognosis. In earlier trials PCI has been associated with more procedure related complications in women than men, but this difference between genders has been less pronounced in more recent studies. In acute coronary syndromes there is no evidence of gender differences regarding the benefit of primary PCI for ST-segment elevation myocardial infarction. However, several trials of unstable angina and non-ST-segment elevation myocardial infarction indicate that women do not have the similar benefit of a routine, early, invasive treatment strategy compared with men.
Review: Endurance exercise and resistance training in cardiovascular disease
Authors: Meka Naga , Katragadda Srikanth , Cherian Biju , Arora Rohit R.
Published: March 2008

Contrary to the age old taboo of exercise in cardiac patients, resistance training has been gaining importance recently as a safe, healthy fitness option in prevention of cardiovascular diseases, the leading killer disease in the population above 45 years in the United States. Endurance or aerobic exercise helps improve overall stamina and the ability of the heart to pump oxygenated blood in those with and without prior cardiovascular disease. In addition to modifying cardiovascular risks, resistance training has profound beneficial effects on improving muscle strength and endurance, preventing osteoporosis and improving quality of life both in the healthy and cardiovascular patients including women and heart failure patients. So resistance training should be regarded as a complementary fitness program rather that a substitute to endurance training. This review discusses the physiological phenomenon and benefits of exercise training programs on cardiovascular disease patients focusing on endurance exercise and resistance training.
Selecting Equipment To Minimize Production Costs and Maximize Profitability
Authors: Smith Dan , Spalding Mark A. , Gould Russell J.
Published: March 2008

Specifying and installing the proper equipment for a process is the key to minimizing the long-term cost of producing products. But often the objective to purchasing equipment is to minimize the initial capital cost. Minimizing this initial purchase cost, however, may require the purchaser to add costly modifications to the line after installation, creating higher operating costs, lengthy troubleshooting, and a delay to market entry. Principles and strategies are presented here that show how to avoid this mistake, and case studies are provided as learning tools.
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

Low-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

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

Neutrophils 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

Using 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

Central 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

The 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

Galectin-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.
Preface
Authors: Sideman Samuel
Published: March 2008

Signaling is part of a complex system of communication that governs basic cellular functions and coordinates cellular activity. Transfer of ions and signaling molecules and their interactions with appropriate receptors, transmembrane transport, and the consequent intracellular interactions and functional cellular response represent a complex system of interwoven phenomena of transport, signaling, conformational changes, chemical activation, and/or genetic expression. The well‐being of the cell thus depends on a harmonic orchestration of all these events and the existence of control mechanisms that assure the normal behavior of the various parameters involved and their orderly expression. The ability of cells to sustain life by perceiving and responding correctly to their microenvironment is the basis for development, tissue repair, and immunity, as well as normal tissue homeostasis. Natural deviations, or human‐induced interference in the signaling pathways and/or inter‐ and intracellular transport and information transfer, are responsible for the generation, modulation, and control of diseases. The present overview aims to highlight some major topics of the highly complex cellular information transfer processes and their control mechanisms. Our goal is to contribute to the understanding of the normal and pathophysiological phenomena associated with cardiac functions so that more efficient therapeutic modalities can be developed. Our objective in this volume is to identify and enhance the study of some basic passive and active physical and chemical transport phenomena, physiological signaling pathways, and their biological consequences.
Genetic Mechanisms Controlling Cardiovascular Development
Authors: Bentham Jamie , Bhattacharya Shoumo
Published: March 2008

Congenital heart disease (CHD) is a major cause of childhood morbidity and death in the West; the incidence is approximately 1 in 145 live births. Mendelian and chromosomal syndromes account for approximately 20% of CHD. The genetic mechanisms underlying non‐chromosomal or non‐Mendelian “sporadic” CHD, which account for the remaining 80%, are poorly understood. The genetic architecture of sporadic CHD likely includes accumulation of rare nonsynonymous variants in cardiac developmental genes leading to mutational loading of cardiac developmental networks, copy number variation in cardiac developmental genes, and common variants that may not be obviously linked to cardiac development but may alter genetic buffering pathways (e.g., folate metabolism). The rare mutations typically associated with sporadic CHD likely arise from the severe decrease in reproductive fitness selecting against any CHD‐causing gene variant. The resulting allelic heterogeneity reduces the power of genome‐wide association studies for CHD. A complementary approach to the genetic analysis of CHD is to resequence candidate genes that have been shown to be necessary for mouse heart development. The number of such genes likely exceeds 1700. To identify these genes, we have developed an enabling technology (high‐throughput magnetic resonance imaging of mouse embryos), which is used in combination with N‐ethyl‐N‐nitrosourea/transposon mutagenesis and knockout techniques. Key future challenges now involve translating discoveries made in mouse models to human CHD genetics and understanding the mechanisms that create and disrupt genetic buffering. A long‐term goal in CHD is to manipulate these pathways to enhance buffering and prevent disease in a manner analogous to the use of folate in preventing neural tube defects.
Neonatal and Adult Cardiovascular Pathophysiological Remodeling and Repair
Authors: Norris Russell A. , Borg Thomas K. , Butcher Jonathan T. , Baudino Troy A. , Banerjee Indroneal , Markwald Roger R.
Published: March 2008

The neonatal heart undergoes normal hypertrophy or compensation to complete development and adapt to increased systolic pressures. Hypertrophy and increased neonatal wall stiffness are associated with a doubling of the number of fibroblasts and de novo formation of collagen. Normal postnatal remodeling is completed within 3–4 weeks after birth but can be rekindled in adult life in response to environmental signals that lead to pathological hypertrophy, fibrosis, and heart failure. The signals that trigger fibroblast and collagen formation (fibrosis) as well as the origin and differentiation of the cardiac fibroblast lineage are not well understood. Using mice studies and a single‐cell engraftment model, we have shown that cardiac fibroblasts are derived from two extracardiac sources: the embryonic proepicardial organ and the recruitment of circulating bone marrow cells of hematopoietic stem cell origin. Periostin, a matricellular protein, is normally expressed in differentiating fibroblasts but its expression is elevated several fold in pathological remodeling and heart failure. Our hypothesis that periostin is profibrogenic (i.e., it promotes differentiation of progenitor mesenchymal cells into fibroblasts and their secretion and compaction of collagen) was tested using isolated and cultured embryonic, neonatal, and adult wild‐type and periostin‐null, nonmyocyte populations. Our findings indicate that abrogation of periostin by targeted gene deletion inhibits differentiation of nonmyocyte progenitor cells or permits misdirection into a cardiomyocyte lineage. However, if cultured with periostin or forced to express periostin, they became fibroblasts. Periostin plays a significant role in promoting fibrogenesis residual stress, and tensile testings indicated that periostin played an essential regulatory role in maintaining the biomechanical properties of the adult myocardium. These findings indicate that periostin is a profibrogenic matricellular protein that promotes collagen fibrogenesis, inhibits differentiation of progenitor cells into cardiomyocytes, and is essential for maintaining the biomechanical properties of the adult myocardium.