bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of Double Flask Investing and Microwave Heating on the Superficial Porosity, Surface Roughness, and Knoop Hardness of Acrylic Resin
Authors: Rizzatti‐Barbosa Celia Marisa , Ribeiro‐Dasilva Margarete C.
Published: April 2009

Purpose: Simultaneous polymerization of maxillary and mandibular complete dentures with teeth in occlusion through investing in a double special flask has been described as a more rapid and efficient method to polymerize prostheses than the conventional method; however, no study has been done to verify important properties of resin, including superficial porosity, surface roughness, and hardness, when processed by this technique. The purpose of this study was to verify if the simultaneous polymerization associated with microwave heating may alter the superficial porosity, surface roughness, and Knoop hardness of acrylic resin.

Materials and Methods: Resin specimens processed in single and double dental flasks were compared using microwave energy and warm water methods. Four groups were tested according to the investing flask and the method of resin cure: Group I control specimens (n = 15) were invested in single metal flasks and cured by warm water at 74°C for 9 hours. Group II (n = 15) specimens were invested in single polyvinyl chloride flasks and cured by microwave energy at 90 W for 20 minutes plus 450 W for 5 minutes. Group III (n = 30) and Group IV (n = 30) specimens were processed by simultaneous polymerization in double flasks and cured by the same warm water and microwave energy protocols, respectively.

Results: No significant differences were found in mean superficial porosity (8.06 ± 2.28 pore/cm2), surface roughness (0.14 ± 0.03 μm), or Knoop hardness (19.66 ± 2.25 kgf/mm2) between the control group (GI), and the other three experimental groups (p > 0.05).

Conclusion: Processing acrylic resin in a double flask heated by either warm water or microwave energy does not alter the resin's superficial porosity, surface roughness, or Knoop hardness; however, other properties of resin should be analyzed using this denture processing technique.
In vitro platelet function of platelet concentrates prepared using three different apheresis devices determined by impedance and optical aggregometry
Authors: Jilma‐Stohlawetz Petra , Eichelberger Beate , Horvath Michaela , Jilma Bernd , Panzer Simon
Published: April 2009

BACKGROUND: Testing the functional capacity of platelets (PLTs) from platelet concentrates (PC) is a main issue in transfusion medicine. Therefore, the aim was to study agonist‐inducible PLT aggregation of PLTs obtained by three apheresis devices. A semiautomated impedance aggregometry‐based whole‐blood method (multiplate electrode PLT aggregometry [MEA]) was modified for the use of PLTs from PC and data were compared with light transmission aggregometry (LTA).

STUDY DESIGN AND METHODS: PLT function was determined in 135 PCs without reconstitution with red blood cells (RBCs), obtained by three devices: Amicus, Trima Accel collection system, and MCS+. PLT function was assessed by the Multiplate TRAP test, and the area under the curve (AUC) was quantified. TRAP‐6–inducible maximal PLT aggregation (MA%) by LTA was used for analyses.

RESULTS: The AUC was significantly lower in the Amicus PLTs compared to the Trima and MCS+ PLTs (Amicus versus Trima, p = 0.007; Amicus versus MCS+, p < 0.001). The Amicus PLTs were significantly less responsive to TRAP‐6–inducible PLT aggregation than Trima (p = 0.002) or MCS+ PLTs (p < 0.001) by LTA, and Trima PLTs responded significantly less than MCS+ PLTs (p = 0.001). There was only a weak correlation between MEA and LTA (r = 0.29, p = 0.019).

CONCLUSION: PLTs obtained by the Amicus system show significantly less aggregation response to thrombin receptor stimulation compared to those obtained with other cell separators, examined by MEA and LTA. Testing PLT function in PCs by the MEA is a simple and rapid method without the need of adding RBCs. However, LTA and MEA appear to measure different aspects of PLT function.
Elevated Ca2+ influx–inducing activity toward mast cells in pretransfusion sera from patients who developed transfusion‐related adverse reactions
Authors: Azuma Hiroshi , Yamaguchi Miki , Takahashi Daisuke , Fujihara Mitsuhiro , Sato Shinichiro , Kato Toshiaki , Ikeda Hisami
Published: April 2009

BACKGROUND: Type I allergic reactions such as urticaria‐like manifestations constitute a large percentage of transfusion‐related adverse events. Along with donor factors, patient factors might be involved in these reactions. Sera from some patients with chronic idiopathic urticaria show histamine‐releasing activity (HRA). Sera from patients who develop Type I allergic reaction might possess HRA.

STUDY DESIGN AND METHODS: Pretransfusion serum samples were collected. Mast cells were cultured from peripheral blood CD34+ cells and mixed with the serum samples. Cells with elevated intracytoplasmic Ca2+ concentrations were monitored using flow cytometry to evaluate Ca2+ influx–inducing activity (CaIA) in serum. The amount of histamine released into the supernatant was measured using an enzyme immunoassay kit to evaluate HRA. In some assays, cells were incubated with pertussis toxin (Ptx).

RESULTS: CaIA values were higher (p < 0.05) in sera from patients with reactions (27.68 ± 20.38 [n = 145]; range, 0.49‐84.90) than in sera of patients without reactions (10.70 ± 6.50 [n = 54]; range, 2.67‐36.97) and control sera (9.67 ± 5.88 [n = 107]; range, 1.11‐25.68). No difference in CaIA was found between patients with (27.38 ± 20.46 [n = 88]) and without (28.38 ± 20.59 [n = 57]) skin manifestations. However, CaIA was higher (p < 0.05) in patients with pure urticaria (mean, 30.58 ± 21.3 [n = 30]; range, 70.43‐4.1) than in patients with fever alone (mean, 18.61 ± 14.71 [n = 18]; range, 45.94‐3.19). Levels of HRA were higher (p < 0.001) in CaIA‐positive sera than in CaIA‐negative sera. Both CaIA and HRA were blocked by Ptx.

CONCLUSION: Elevated CaIA and HRA in pretransfusion sera might be attributable to adverse reactions, especially to urticaria‐like manifestation. The Gi protein–coupled receptor complexes on mast cells and its ligand must be involved.
What type of information is trusted by whom? A multilevel analysis of the stability of the information source‐trust association for blood transfusion
Authors: Ferguson Eamonn , Spence Alexa , Townsend Ellen , Prowse Chris , Palmer Joyce , Fleming Piers , Van Hilten Joost A.
Published: April 2009

BACKGROUND: It has been suggested that transfusion information from scientific sources (vs. popular sources) is seen as more trustworthy and that interventions should consider using scientific styles. Before such suggestions can be implemented, it is necessary to know if this science source‐trust link is observed across different sociodemographic groups and psychological characteristics. A large‐scale field‐based study examining the importance of sociodemographics and psychological characteristics on the source‐trust link was conducted.

STUDY DESIGN AND METHODS: A large field‐based experiment (the Euro Blood Substitutes Project) was conducted on four different samples (the general public, blood donors, patients, and health experts) in the UK and The Netherlands (total n = 3935). Questions examined levels of trust about sources of transfusion medicine, various aspects of knowledge, and demographic data.

RESULTS: People differentiated between scientific and popular sources, with scientific sources perceived as more trustworthy. General trust in transfusion medicine was higher for those who believe that they or scientists were knowledgeable about transfusion medicine or genetic modification (GM). This suggests that people do not differentiate in their subjective knowledge between GM and transfusion medicine. This science trust‐source relationship was moderated by a variety of demographic (e.g., younger people were more likely to trust scientific sources) and psychological (e.g., those who rate science as knowledgeable were more trusting of scientific sources) factors.

CONCLUSION: The trust‐source link is not stable and communications should be targeted to the specific population samples for which they will be most effective; scientifically styled information will be particularly effective for communicating information within certain populations.
Molecular bases of unexpressed RHD alleles in Chinese D− persons
Authors: Ye Luyi , Yue Danqi , Wo Dele , Ding Xiyu , Guo Shuangmei , Li Qin , Guo Zhonghui , Zhu Ziyan
Published: April 2009

BACKGROUND: The aim of this study was to use a systematic survey to analyze RHD alleles in Chinese D− donors who do not express D antigen or who lack functional RhD protein.

STUDY DESIGN AND METHODS: A total of 733 D− Chinese donors, not including Del phenotypes, were investigated by RHD polymorphism–specific polymerase chain reaction (PCR), Rhesus box PCR‐PstI digestion, and RHD sequencing. The frequencies of identified alleles were calculated.

RESULTS: Three genetic mechanisms and eight alleles were found associated with the Chinese D− phenotype. One new RHD/CE hybrid allele and one novel mutation were also found. The rates of total deletion and the most frequent hybrid allele RHD(1)‐CE(2‐9)‐D(10) were similar to those found in previous studies. A previously reported mutation RHD(711delC) was found to be the predominant cause of aberrant RHD alleles.

CONCLUSION: Informative population‐based data for improving molecular diagnostic strategies for Chinese D− persons are suggested by this study. This type of systematic knowledge is important for the development of typing and transfusion strategies for the Chinese population.
Research opportunities for pathogen reduction/inactivation of blood components: summary of an NHLBI workshop
Authors: Klein Harvey G. , Glynn Simone A. , Ness Paul M. , Blajchman Morris A.
Published: April 2009

In July 2008, a workshop sponsored by the Division of Blood Diseases and Resources of the National Heart, Lung, and Blood Institute (NHLBI) was convened to identify potential research opportunities that could advance our understanding of both the biologic and the clinical impact of the various available pathogen reduction/inactivation (PR/PI) methods of blood components (platelets [PLTs], red blood cells, and plasma) intended for allogeneic transfusion. These discussions resulted in consensus that, even though several PR/PI technologies have already been licensed and are being used in Europe and elsewhere for PLTs and plasma, concerns about possible side effects, particularly component quality and pulmonary toxicity, have impeded regulatory approval in North America (United States and Canada). Such concerns thus threaten to stall further development of these technologies. As a consequence, the NHLBI workshop participants focused on formulating a series of research‐related recommendations to better understand, mitigate, and prevent these adverse effects. Other important issues identified included the need for a single method to inactivate pathogens in whole blood without damaging the various blood components; new ways to monitor the efficacy of treated components, including animal models to screen for safety; a better understanding of the effect of PR/PI‐treated products on recipient alloimmunization, tolerance, and immune modulation; understanding the impact of PR/PI on various other noninfectious hazards of transfusion; and establishing methods to evaluate risk‐benefit and cost‐effectiveness, in particular with reference to emerging pathogens. The working group also discussed issues related to specific blood components, such as improving the process of clinical evaluation, investigating the impact of PR/PI on component storage lesions, understanding mechanisms that reduce component viability, and addressing the underlying resistance to the adoption of PR/PI‐treated components. This communication summarizes the opinions of workshop participants on these issues and concludes with a list of areas for possible research that could advance the application of PR/PI methods to enhance the safety of the world's blood supplies.
Interactions between Corporate Agency Conflicts
Authors: Douglas Alan V. S.
Published: April 2009

This paper examines simultaneous incentive conflicts between shareholders, bondholders, and managers. Manager‐owner conflicts arise from information asymmetries, and interact with traditional shareholder‐bondholder conflicts (i.e., underinvestment and asset substitution conflicts). Managers are aligned with the bondholders' preference to avoid underinvestment, but are aligned with the shareholders' preference for asset substitution, to the extent that riskier investments increase the manager's information advantage. The interactions between conflicts extend the agency cost literature and facilitate empirical implications linking the influence of each party to investment opportunities, financial policy, compensation contracts, and firm value.
Prescriptions for Schedule II Opioids and Benzodiazepines Increase after the Introduction of Computer‐generated Prescriptions
Authors: McGerald Genevieve , Dvorkin Ronald , Levy David , Lovell‐Rose Stephanie , Sharma Adhi
Published: April 2009

Background:  Prescriptions for controlled substances decrease when regulatory barriers are put in place. The converse has not been studied.

Objectives:  The objective was to determine whether a less complicated prescription writing process is associated with a change in the prescribing patterns of controlled substances in the emergency department (ED).

Methods:  The authors conducted a retrospective nonconcurrent cohort study of all patients seen in an adult ED between April 19, 2005, and April 18, 2007, who were discharged with a prescription. Prior to April 19, 2006, a specialized prescription form stored in a locked cabinet was obtained from the nursing staff to write a prescription for benzodiazepines or Schedule II opioids. After April 19, 2006, New York State mandated that all prescriptions, regardless of schedule classification, be generated on a specialized bar‐coded prescription form. The main outcome of the study was to compare the proportion of Schedule III–V opioids to Schedule II opioids and benzodiazepines prescribed in the ED before and after the introduction of a less cumbersome prescription writing process.

Results:  Of the 26,638 charts reviewed, 2.1% of the total number of prescriptions generated were for a Schedule II controlled opioid before the new system was implemented compared to 13.6% after (odds ratio [OR] = 7.3, 95% confidence interval [CI] = 6.4 to 8.4). The corresponding percentages for Schedule III–V opioids were 29.9% to 18.1% (OR = 0.52, 95% CI = 0.49 to 0.55) and for benzodiazepines 1.4% to 3.9% (OR = 2.8, 95% CI = 2.4 to 3.4).

Conclusions:  Patients were more likely to receive a prescription for a Schedule II opioid or a benzodiazepine after a more streamlined computer‐generated prescription writing process was introduced in this ED.
Cardiac renewing: interstitial Cajal‐like cells nurse cardiomyocyte progenitors in epicardial stem cell niches
Authors: Popescu L. M. , Gherghiceanu Mihaela , Manole C. G. , Faussone‐Pellegrini Maria Simonetta
Published: April 2009

Recent studies suggested that various cell lineages exist within the subepicardium and we supposed that this area could host cardiac stem cell niches (CSCNs). Using transmission electron microscopy, we have found at least 10 types of cells coexisting in the subepicardium of normal adult mice: adipocytes, fibroblasts, Schwann cells and nerve fibres, isolated smooth muscle cells, mast cells, macrophages, lymphocytes, interstitial Cajal‐like cells (ICLCs) and cardiomyocytes progenitors (CMPs). The latter cells, sited in the area of origin of coronary arteries and aorta, showed typical features of either very immature or developing cardiomyocytes. Some of these cells were connected to each other to form columns surrounded by a basal lamina and embedded in a cellular network made by ICLCs. Complex intercellular communication occurs between the ICLCs and CMPs through electron‐dense nanostructures or through shed vesicles. We provide here for the first time the ultrastructural description of CSCN in the adult mice myocardium, mainly containing ICLCs and CMPs. The existence of resident CMPs in different developmental stages proves that cardiac renewing is a continuous process. We suggest that ICLCs might act as supporting nurse cells of the cardiac niches and may be responsible for activation, commitment and migration of the stem cells out of the niches. Briefly, not only resident cardiac stem cells but also ICLCs regulate myocyte turnover and contribute to both cardiac cellular homeostasis and endogenous repair/remodelling after injuries.
HIV and SIV infection: the role of cellular restriction and immune responses in viral replication and pathogenesis
Authors: WILLIAMS KENNETH C. , BURDO TRICIA H.
Published: April 2009

The human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) have a long biological history. Both viruses evolved from Africa and remnants of them can be found in the ‘fossil record’ of several species in which they are not endemic. SIV remains endemic in several species of monkeys in Africa where it does not cause immune deficiency. HIV and SIV actively replicate within humans and Asian non‐human primates, despite cellular and genetic viral restriction factors and genes, and at times robust innate and adaptive immune responses. While Lentiviruses are considered ‘slow viruses’ it is clear in humans and susceptible Asian monkeys that virus production is rapid and highly active. This results in a massive loss of CD4+ memory effector T cells early after infection and a continued race between viral evolution, cytotoxic lymphocytes, and failed neutralizing antibody responses. Concurrently, HIV and SIV can infect monocyte/macrophage populations in blood and more importantly in tissues, including the central nervous system, where the virus can remain sequestered and not cleared by anti‐retroviral therapy, and hide for years. This review will discuss species and cellular barriers to infection, and the role of innate and acquired immunity with infection and pathogenesis of HIV and SIV in select species.
Co‐ordinating innate and adaptive immunity to viral infection: mobility is the key
Authors: CHRISTENSEN JEANETTE ERBO , THOMSEN ALLAN RANDRUP
Published: April 2009

The host counters a viral infection through a complex response made up of components belonging to both the innate and the adaptive immune system. In this report, we review the mechanisms underlying this response, how it is induced and how it is co‐ordinated. As cell–cell communication represents the very essence of immune system physiology, a key to a rapid, efficient and optimally regulated immune response is the ability of the involved cells to rapidly shift between a stationary and a mobile state, combined with stringent regulation of cell migration during the mobile state. Through the co‐ordinated recruitment of different cell types intended to work in concert, cellular co‐operation is optimized particularly under conditions that may involve rare cells. Consequently, a major focus is placed on presenting an overview of the co‐operative events and the associated cell migration, which is essential in mounting an efficient host response and co‐ordinating innate and adaptive immunity during a primary viral infection.
Cooperation and conflict in host–microbe relations
Authors: ULVESTAD ELLING
Published: April 2009

Hosts and microbes associate in a variety of relations along a continuum ranging from symbiotic to pathogenic. Defence mechanisms have been evolutionarily selected in both hosts and microbes to protect the organism's integrity. Such defences have to be utilized with caution. They must be adapted to the tasks at hand; otherwise any symbiotic relation would be impossible. To explain this cautionary use of defences we need to understand how life on Earth evolved into cooperative and competing entities at various levels of organization. The purpose of this article is to review theory and selected mechanisms relating to the evolution and development of host–microbe interactions, with special emphasis on host responses. The rationale is that without theory, extrapolations from misleading observations can dominate and distort, for a significant time, the course of a scientific field. The argument is set forth that social evolution theory provides a conceptual framework for addressing questions relating to interaction between hosts and microbes. The article is a partial summary of arguments presented in my book Defending life – the nature of host–parasite relations.
Interaction of Mycobacterium tuberculosis with the host: consequences for vaccine development
Authors: DIETRICH JES , DOHERTY T. MARK
Published: April 2009

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), remains a major worldwide health problem that causes more than 2 million deaths annually. In addition, an estimated 2 billion people are latently infected with M. tuberculosis. The bacterium is one of the oldest human pathogens and has evolved complex strategies for survival. Therefore, to be successful in the high endemic regions, any future TB vaccine strategy will have to be tailored in accordance with the resulting complexity of the TB infection and anti‐mycobacterial immune response. In this review, we will discuss what is presently known about the interaction of M. tuberculosis with the immune system, and how this knowledge is used in new and more advanced vaccine strategies.
Virus‐specific CD8 T cells: activation, differentiation and memory formation
Authors: WIESEL MELANIE , WALTON SENTA , RICHTER KIRSTEN , OXENIUS ANNETTE
Published: April 2009

CD8 T cells are pivotal for the control of many intracellular pathogens, and besides their role in immediate control of infections, CD8 T cells have the capacity to differentiate into long‐lived antigen‐independent memory CD8 T cells, at least in situations of acute and resolved infections. The population of memory cells is heterogeneous with respect to their phenotype, their anatomical localization and their functional capacities in order to afford optimal protection against secondary infections. In the past years, it has become clear that multiple in vivo parameters are involved in shaping the composition of the memory CD8 T cell population, including antigen load, duration and strength of CD8 T cell stimulation, the level of inflammation, availability of CD4 T cell help and CD8 T cell precursor frequencies. With respect to the timing when CD8 T cells are committed to become memory cells, several models have been proposed. In contrast to acute, resolved infection, the continued in vivo exposure to high levels of antigen during persistent chronic viral infection precludes the development of long‐lived antigen‐independent memory CD8 T cells and might even result in severe dysfunction of virus‐specific CD8 T cells.
Putting density dependence in perspective: nest density, nesting phenology, and biome, all matter to survival of simulated mallard Anas platyrhynchos nests
Authors: Elmberg Johan , Folkesson Karin , Guillemain Matthieu , Gunnarsson Gunnar
Published: April 2009

Breeding success in ground‐nesting birds is primarily determined by nest survival, which may be density‐dependent, but the generality of this pattern remains untested. In a replicated crossover experiment conducted on 30 wetlands, survival of simulated mallard nests was related to “biome” (n=14 mediterranean and 16 boreal wetlands), breeding “phenology” (early vs late nests), and “density” (2 vs 8 nests per 225 m shoreline). Local abundances of “waterfowl”, “other waterbirds”, and “avian predators” were used as covariates. We used an information‐theoretic approach and Program MARK to select among competing models. Nest survival was lower in late nests compared with early ones, and it was lower in the mediterranean than in the boreal study region. High‐density treatment nests suffered higher depredation rates than low‐density nests during days 1–4 of each experimental period. Nest survival was negatively associated with local abundance of “waterfowl” in the boreal but not in the mediterranean biome. Effect estimates from the highest‐ranked model showed that nest “density” (d 1–4) had the strongest impact on model fit; i.e. three times that of “biome” and 1.5 times that of “phenology”. The latter′s effect, in turn, was twice that of “biome”. We argue that our study supports the idea that density‐dependent nest predation may be temporally and spatially widespread in waterfowl. We also see an urgent need for research of how waterfowl nesting phenology is matched to that of prey and vegetation.
A patch perspective on summer habitat use by brown trout Salmo trutta in a high plains stream in Wyoming, USA
Authors: O’Connor R. R. , Rahel F. J.
Published: April 2009

Abstract –  We quantified the use of habitat patches by brown trout, Salmo trutta, during summer conditions in a plains stream in the western United States. A Global Positioning System was used to map discrete habitat patches (2–420 m2) consisting of macrophytes, wood accumulation, or deep water. Habitat use by brown trout was monitored by radio telemetry. Brown trout used habitat in a nonrandom manner with 99% of all daytime observations and 91% of all nighttime observations occurring in patches that consisted of combinations of deep water, wood accumulations or macrophytes even though such patches constituted only 9.8% of the available habitat. Brown trout used deep water almost exclusively during the day but broadened their habitat use at night. Most fish stayed within a large plunge pool created by a low‐head dam. This pool supplemented the deep‐water habitat that was naturally rare in our study area and illustrates how human modifications can sometimes create habitat patches important for stream fishes.
Immunoregulation by tumor necrosis factor superfamily member LIGHT
Authors: Wang Yugang , Zhu Mingzhao , Miller Mendy , Fu Yang‐Xin
Published: April 2009

Summary:  LIGHT (homologous to lymphotoxins, inducible expression, competes with herpesvirus glycoprotein D for herpesvirus entry mediator, a receptor expressed on T lymphocytes) is a member of the tumor necrosis factor superfamily that contributes to the regulation of immune responses. LIGHT can influence T‐cell activation both directly and indirectly by engagement of various receptors that are expressed on T cells and on other types of cells. LIGHT, LIGHT receptors, and their related binding partners constitute a complicated molecular network in the regulation of various processes. The molecular cross‐talk among LIGHT and its related molecules presents challenges and opportunities for us to study and to understand the full extent of the LIGHT function. Previous research from genetic and functional studies has demonstrated that dysregulation of LIGHT expression can result in the disturbance of T‐cell homeostasis and activation, changing the ability of self‐tolerance and of the control of infection. Meanwhile, blockade of LIGHT activity can ameliorate the severity of various T‐cell‐mediated diseases. These observations indicate the importance of LIGHT and its involvement in many physiological and pathological conditions. Understanding LIGHT interactions offers promising new therapeutic strategies that target LIGHT‐engaged pathways to fight against cancer and various infectious diseases.
Negative regulators of T‐cell activation: potential targets for therapeutic intervention in cancer, autoimmune disease, and persistent infections
Authors: Pentcheva‐Hoang Tsvetelina , Corse Emily , Allison James P.
Published: April 2009

Summary:  The generation of productive adaptive immune responses depends on the antigen‐specific activation of T and B cells. The outcome of T‐cell receptor engagement is influenced by signals from both positive and negative regulatory molecules that can either activate or inhibit T‐cell function. CD28 and cytotoxic T‐lymphocyte antigen‐4 are the prototypical members of an immunoglobulin domain‐containing protein family that play important roles in the control of T‐cell responses against infection, cancer, and in autoimmune disease. Although the precise molecular details of their functions are still under active investigation, tumors and chronic pathogens seem to have exploited these pathways to achieve immune evasion. Furthermore, malfunction of the inhibitory arm of the immune response appears responsible for the development of multiple autoimmune pathologies. As a result, the negative regulators of T‐cell activation have become attractive targets for therapeutic intervention in cancer, chronic infection, and autoimmune disease. The application of findings from basic research has provided insight into the manipulation of these pathways in the clinic and offers promising strategies for the treatment of disease.
Immune regulation by 4‐1BB and 4‐1BBL: complexities and challenges
Authors: Wang Chao , Lin Gloria H. Y. , McPherson Ann J. , Watts Tania H.
Published: April 2009

Summary:  The tumor necrosis factor receptor family member 4‐1BB plays a key role in the survival of activated and memory CD8+ T cells. Depending on the disease model, 4‐1BB can participate at different stages and influence different aspects of the immune response, likely due to the differential expression of receptor and ligand relative to other costimulatory molecules. Studies comparing mild versus severe influenza infection of mice suggest that the immune system uses inducible receptors such as 4‐1BB to prolong the immune response when pathogens take longer to clear. The expression of 4‐1BB on diverse cell types, evidence for bidirectional as well as receptor‐independent signaling by 4‐1BBL, the unexpected hyperproliferation of 4‐1BB‐deficient T cells, and complex effects of agonistic anti‐4‐1BB therapy have revealed additional roles for the 4‐1BB/4‐1BBL receptor/ligand pair in the immune system. In this review, we discuss these diverse roles of 4‐1BB and its ligand in the immune response, exploring possible mechanisms for the observed complexities and implications for therapeutic applications of 4‐1BB/4‐1BBL.
The significance of OX40 and OX40L to T‐cell biology and immune disease
Authors: Croft Michael , So Takanori , Duan Wei , Soroosh Pejman
Published: April 2009

Summary:  OX40 (CD134) and its binding partner, OX40L (CD252), are members of the tumor necrosis factor receptor/tumor necrosis factor superfamily and are expressed on activated CD4+ and CD8+ T cells as well as on a number of other lymphoid and non‐lymphoid cells. Costimulatory signals from OX40 to a conventional T cell promote division and survival, augmenting the clonal expansion of effector and memory populations as they are being generated to antigen. OX40 additionally suppresses the differentiation and activity of T‐regulatory cells, further amplifying this process. OX40 and OX40L also regulate cytokine production from T cells, antigen‐presenting cells, natural killer cells, and natural killer T cells, and modulate cytokine receptor signaling. In line with these important modulatory functions, OX40–OX40L interactions have been found to play a central role in the development of multiple inflammatory and autoimmune diseases, making them attractive candidates for intervention in the clinic. Conversely, stimulating OX40 has shown it to be a candidate for therapeutic immunization strategies for cancer and infectious disease. This review provides a broad overview of the biology of OX40 including the intracellular signals from OX40 that impact many aspects of immune function and have promoted OX40 as one of the most prominent costimulatory molecules known to control T cells.
Costimulatory and coinhibitory receptors in anti‐tumor immunity
Authors: Driessens Gregory , Kline Justin , Gajewski Thomas F.
Published: April 2009

Summary:  Despite the expression of antigens by tumor cells, spontaneous immune‐mediated rejection of cancer seems to be a rare event. T‐cell receptor engagement by peptide/major histocompatibility complexes constitutes the main signal for the activation of naive T cells but is not sufficient to initiate a productive generation and maintenance of effector cells. Full activation of T cells requires additional signals driven by costimulatory molecules present on activated antigen‐presenting cells but rarely on tumors. Following the discovery of B7‐1 (CD80), several other costimulatory molecules have been shown to contribute to T‐cell activation and have relevance for improving anti‐tumor immunity. Moreover, increasing the understanding of coinhibitory receptors has highlighted key additional pathways that can dominantly inhibit anti‐tumor T‐cell function. Improving positive costimulation, and interfering with negative regulation, continues to represent an attractive immunotherapeutic approach for the treatment of cancer. This review focuses upon those pathways with the highest potential for clinical application in human cancer patients.
Autoimmunity risk alleles in costimulation pathways
Authors: Maier Lisa M. , Hafler David A.
Published: April 2009

Summary:  The basis for susceptibility to common autoimmune diseases is a complex interplay between multiple genetic and environmental risk factors. We have now entered a new generation of genetic study designs which has not only furthered our understanding of the individual mechanisms involved in the common human autoimmune diseases but also has pointed towards common pathways. In this review we focus on costimulatory mechanisms with the most convincing association results in large collections of patients and control subjects. These include the genes encoding cytotoxic T‐lymphocyte antigen‐4, CD58, CD40, inducible T‐cell costimulator ligand, CD244, CD226, tumor necrosis factor (TNF) (ligand) superfamily member 4, TNF superfamily member 15, and programmed cell death 1. The unbiased genome‐wide association scans suggest that indeed immune related genes underlie the pathogenesis of human autoimmune disease with common involvement of costimulatory pathways. The identification of allelic variants associated with disease risk followed by understanding their functional outcomes and affected pathways provides a rationale approach for drug design.
Sequence, structure, function, immunity: structural genomics of costimulation
Authors: Chattopadhyay Kausik , Lazar‐Molnar Eszter , Yan Qingrong , Rubinstein Rotem , Zhan Chenyang , Vigdorovich Vladimir , Ramagopal Udupi A. , Bonanno Jeffrey , Nathenson Stanley G. , Almo Steven C.
Published: April 2009

Summary:  Costimulatory receptors and ligands trigger the signaling pathways that are responsible for modulating the strength, course, and duration of an immune response. High‐resolution structures have provided invaluable mechanistic insights by defining the chemical and physical features underlying costimulatory receptor:ligand specificity, affinity, oligomeric state, and valency. Furthermore, these structures revealed general architectural features that are important for the integration of these interactions and their associated signaling pathways into overall cellular physiology. Recent technological advances in structural biology promise unprecedented opportunities for furthering our understanding of the structural features and mechanisms that govern costimulation. In this review, we highlight unique insights that have been revealed by structures of costimulatory molecules from the immunoglobulin and tumor necrosis factor superfamilies and describe a vision for future structural and mechanistic analysis of costimulation. This vision includes simple strategies for the selection of candidate molecules for structure determination and highlights the critical role of structure in the design of mutant costimulatory molecules for the generation of in vivo structure–function correlations in a mammalian model system. This integrated ‘atoms‐to‐animals’ paradigm provides a comprehensive approach for defining atomic and molecular mechanisms.
The clinical utility of inhibiting CD28‐mediated costimulation
Authors: Linsley Peter S. , Nadler Steven G.
Published: April 2009

Summary:  This volume covers many topics in the field of T‐cell costimulation. The need for such a volume is testament to the growth of the field. From its beginning as a concept in the 1980s, we have now progressed to the point where many molecules now have functionally defined roles in T‐cell costimulation. In addition, the field has progressed ‘from bench to bedside’. Abatacept [cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4)‐immunoglobulin (Ig) (CTLA‐4‐Ig)], an inhibitor of CD28‐mediated T‐cell costimulation, was approved for the treatment of moderate‐to‐severe rheumatoid arthritis in 2006 by the Food and Drug Administration and in 2007 by the European Medicines Agency. This chapter first presents a personal historical perspective on the early basic studies on the elucidation of the CD28/B7 T‐cell costimulatory pathway and the discovery of CTLA‐4‐Ig. We next present an overview of studies of CTLA‐4‐Ig in preclinical animal studies. The material discussed in these first two sections is selective rather than exhaustive; their purpose is to provide context for the final section, a summary of human clinical studies performed with abatacept.
Costimulatory pathways in transplantation: challenges and new developments
Authors: Li Xian C. , Rothstein David M. , Sayegh Mohamed H.
Published: April 2009

Summary:  T cells are central to graft rejection, and therefore preventing T cells from recognizing and destroying allografts remains an important area of transplant research. However, T cells are also required for transplant tolerance; a subset can enforce a state of tolerance by functioning as regulatory cells. As both rejection and regulation directed against alloantigens require T‐cell activation, costimulatory molecules undoubtedly play an important role in regulating both processes and ultimately the fate of the allograft. However, costimulation involves an incredibly complex array of interactions that may act contemporaneously or at different times; these interactions can have additive or opposing effects on T‐cell activation or differentiation. While some costimulatory molecules mediate activation of naive T cells or generation of memory T cells, others inhibit T‐cell activation and promote anergy or apoptosis. Moreover, a given pathway can have diametrically different effects on T‐effector cells and regulatory T cells (Tregs). Such a complexity presents both challenges and opportunities in targeting T‐cell costimulatory pathways to promote transplant tolerance. In this review article, we provide a summary of recent advances in our understanding of T‐cell costimulatory pathways in regulating different phases of the T‐cell response in transplant models. We focus specifically on costimulatory molecules in the immunoglobulin (Ig) superfamily, tumor necrosis factor (TNF)/TNF receptor superfamily, and in the emerging T‐cell Ig domain and mucin domain family (TIM), highlighting their unique and redundant roles in regulating the T‐effector and Treg responses after transplantation. Finally, we summarize emerging approaches toward inducing tolerance by tipping the balance between cytopathic T‐effector cells and protective Tregs by selectively targeting specific T‐cell costimulatory pathways that are critically involved.
The EGFR‐GEP100‐Arf6‐AMAP1 Signaling Pathway Specific to Breast Cancer Invasion and Metastasis†
Authors: Sabe Hisataka , Hashimoto Shigeru , Morishige Masaki , Ogawa Eiji , Hashimoto Ari , Nam Jin‐Min , Miura Koichi , Yano Hajime , Onodera Yasuhito
Published: April 2009

Tumors are tissue‐specific diseases, and their mechanisms of invasion and metastasis are highly diverse. In breast cancer, biomarkers that specifically correlate with the invasive phenotypes have not been clearly identified. A small GTPase Arf6 primarily regulates recycling of plasma membrane components. We have shown that Arf6 and its effector AMAP1 (DDEF1, DEF1, ASAP1 and centaurin β4) are abnormally overexpressed in some breast cancers and used for their invasion and metastasis. Overexpression of these proteins is independent of the transcriptional upregulation of their genes, and occurs only in highly malignant breast cancer cells. We recently identified GEP100 (BRAG2) to be responsible for the Arf6 activation to induce invasion and metastasis, by directly binding to ligand‐activated epidermal growth factor receptor (EGFR). A series of our studies revealed that for activation of the invasion pathway of EGFR, it is prerequisite that Arf6 and AMAP1 both are highly overexpressed, and that EGFR is activated by ligands. Pathological analyses indicate that a significant large population of human ductal cancers may utilize the EGFR‐GEP100‐Arf6‐AMAP1 pathway for their malignancy. Microenvironments have been highly implicated in the malignancy of mammary tumors. Our results reveal an aspect of the precise molecular mechanisms of some breast cancers, in which full invasiveness is not acquired just by intracellular alterations of cancer cells, but extracellular factors from microenvironments may also be necessary. Possible translation of our knowledge to cancer therapeutics will also be discussed.
Evaluation of chlorhexidine substantivity on salivary flora by epifluorescence microscopy
Authors: Tomás I , García‐Caballero L , Cousido MC , Limeres J , Álvarez M , Diz P
Published: April 2009

Objective:  To evaluate the in vivo antimicrobial activity of chlorhexidine (CHX) in saliva 7 h after its application using an epifluorescence microscopy technique.

Subjects and methods:  Fifteen volunteers performed a single mouthrinse with sterile water (SM‐water) and with 0.2% CHX (SM‐0.2% CHX). Saliva samples were taken at 30 s and 1, 3, 5 and 7 h after each application. The bacterial suspension was mixed with the SYTO 9/propidium iodide staining and observed using an Olympus BX51 microscope. The mean percentage of viable bacteria was calculated for each sample.

Results:  In comparison with baseline values, the frequency of viable bacteria decreased significantly at 30 s after the SM‐0.2% CHX (P < 0.001) and presented significant antibacterial activity up to 7 h after the mouthrinse (P < 0.001). In comparison with SM‐water, the prevalence of viable bacteria was significantly lower at 30 s after the SM‐0.2% CHX (P < 0.001) and showed a significant antibacterial effect up to 7 h after the mouthrinse (P < 0.001).

Conclusions:  Epifluorescence microscopy permits evaluating the antimicrobial activity of CHX on the salivary flora in real‐time. Fluorescence assays could be particularly useful to analyse simultaneously the effect of antimicrobials that alter the cytoplasmic membrane integrity on different oral ecosystems.
Complications during root canal irrigation
Authors: HÜLSMANN MICHAEL , RÖDIG TINA , NORDMEYER SABINE
Published: April 2009

Although endodontic irrigants are generally considered to be safe, severe complications can occur during or as a consequence of root canal irrigation. However, no data on the incidence of irrigation incidents could be found. In the following paper, a review is presented on the possible incidents that may occur during root canal irrigation with different irrigation solutions, the sequelae, as well as prevention and therapy of such intra‐ and post‐operative problems.
Anatomy of an overfill: a reflection on the process
Authors: GLUSKIN ALAN H.
Published: April 2009

The design and implementation of shaping, cleaning and sealing objectives in root canal therapy are fraught with real and potential pitfalls when the anatomic complexity of the space and technical considerations for its instrumentation, disinfection and obturation are contemplated. This review will focus on the genesis of results that lead to endodontic overfills. We will look at how the literature defines overfill and overextension; attempt to address the consensus opinion on the definition of working length; and determine the effects of shaping geometry on overfill as well as the biological impact of obturation materials that go beyond the root canal space. In addition, this manuscript will highlight evidence for the prevention of overfills as well as focus on the local factors that affect repair and healing.
Occupational airborne contact allergy to tetrazepam in a geriatric nurse
Authors: Breuer Kristine , Worm Margitta , Skudlik Christoph , Schröder Claudia , John Swen Malte
Published: April 2009

A 52‐year‐old geriatric nurse presented with recurrent eczema localized in uncovered skin areas. Patch testing produced an eczematous skin reaction with type IV sensitization to tetrazepam. A relapse of contact dermatitis was successfully prevented by using occupational skin protection measures and organizational measures. Our case indicates that a sensitization to drugs should be considered when allergic contact dermatitis is suspected in nursing personnel.
Predicting health‐related quality of life of parents of children with inherited metabolic diseases
Authors: Hatzmann Janneke , Valstar Marlies J , Bosch Annet M , Wijburg Frits A , Heymans Hugo SA , Grootenhuis Martha A
Published: April 2009

Aim:  The aim of this study was to examine medical, socio‐demographic and psychosocial determinants of health‐related quality of life (HRQoL) of parents of children with metabolic diseases.

Methods:  A survey among parents of children with metabolic diseases (children aged 1–19 years, diagnosed >1 year before the start of the study, living at home). Parents were approached through the Emma Children's Hospital, and through a national parent and patient association. HRQoL was assessed using the TNO‐AZL Questionnaire for Adult's Health Related Quality of Life (TAAQOL), describing 12 domains of HRQoL. Predictor variables were taken from a self‐report questionnaire. Univariate and multivariate logistic regression analyses were performed to predict which parents were at risk for HRQoL impairment.

Results:  Mainly psychosocial determinants were predictive for parental HRQoL. Emotional support was protective for parental HRQOL while loss of friendship was a risk factor for HRQoL impairment. Medical and socio‐demographic variables did not consistently predict parental HRQoL.

Conclusion:  Psychosocial determinants appeared more important in predicting parental HRQoL than medical and socio‐demographic variables. Interventions should be focused on supporting parents combining the care for their children with a social life. Further research on this subject is necessary. In the meantime, involved medical specialists should pay structural attention to parental functioning.
Genetic polymorphisms in Thai neonates with hyperbilirubinemia
Authors: Prachukthum Sariya , Nunnarumit Pracha , Pienvichit Paneeya , Chuansumrit Ampaiwan , Songdej Daunthida , Kajanachumpol Saowanee , Pakakasama Samart , Hongeng Suradej
Published: April 2009

Aim:  Polymorphisms of the UGT1A1 gene, SLCO1B1 gene and GST gene have been associated with significant hyperbilirubinemia. We would like to determine whether the variation of UGT1A1 gene, SLCO1B1 gene and GST gene may play a significant role in neonatal hyperbilirubinemia in Thai infants.

Methods:  Ninety‐one study subjects (hyperbilirubinemic group) and 86 control subjects were studied.

Results:  The cause of neonatal hyperbilirubinemia could not be identified in 64 infants (70.3%), ABO blood group incompatibility in 14.3% and Glucose‐6‐phosphate dehydrogenase (G‐6‐PD) deficiency in 8.8%. In the hyperbilirubinemic group, 23 of 91 (25.3%) infants demonstrated variant of UGT1A1 at nucleotides (nt) 211 as compared to 6 of 86 (7%) in the control group (p = 0.001). There were no significant differences between groups in the variants UGT1A1 at nt 686, SLCO1B1 gene at nt 388, 463 and the GST gene. Male infants with G‐6‐PD deficiency were associated with hyperbilirubinemia (21.2% vs. 4.8% in the control group) with an odds ratio (OR) of 5.37 (p =0.02). The relationship between G‐6‐PD and variant in UGT1A1 gene at nt 211 could not be determined.

Conclusion:  Thai infants with variant in the UGT1A1 at nt 211 or with G‐6‐PD deficiency are at higher risk for developing neonatal hyperbilirubinemia.