bluuebunny/crossref_metadata_2025 huggingface dataset:
The Euro-Phospholipid project: epidemiology of the antiphospholipid syndrome in Europe
Authors: Cervera R , Boffa M-C , Khamashta MA , Hughes GRV
Published: August 2009

The Euro-Phospholipid project started in 1999 with a multicentre, consecutive and prospective design. A total cohort of 1000 patients with antiphospholipid syndrome (APS), derived from 13 countries (Belgium, Bulgaria, Denmark, France, Germany, Greece, Hungary, Israel, Italy, the Netherlands, Portugal, Spain and United Kingdom), has been followed since then. This project allowed the identification of the prevalence and characteristics of the main clinical and immunological manifestations at the onset and during the evolution of APS and demonstrated that it is possible to recognize more homogeneous subsets of clinical significance. Patients with APS associated with systemic lupus erythematosus (SLE) had more episodes of arthritis, livedo reticularis and more frequently exhibited thrombocytopenia and leucopenia. Female patients had more episodes of arthritis and livedo reticularis – both connected with the higher prevalence of migraine and SLE-related APS in women, while male patients had more myocardial infarction, epilepsy and lower limb arterial thrombosis. Childhood onset patients presented more episodes of chorea and jugular vein thrombosis, whereas older onset patients were more frequently male and had more strokes and angina pectoris, but less frequently livedo reticularis.
The CAPS Registry: morbidity and mortality of the catastrophic antiphospholipid syndrome
Authors: Bucciarelli S , Espinosa G , Cervera R
Published: August 2009

Although less than 1% of patients with the antiphospholipid syndrome (APS) develop the catastrophic variant, its potentially lethal outcome emphasises its importance in clinical medicine today. However, the rarity of this variant makes it extraordinarily difficult to study in any systematic way. To put together all the published case reports as well as the new diagnosed cases from all over the world, an international registry of patients with catastrophic APS (CAPS Registry) was created in 2000 by the European Forum on Antiphospholipid Antibodies. Currently, it documents the entire clinical, laboratory and therapeutic data of more than 300 patients whose data has been fully registered. This registry can be freely consulted at the Internet (http://www.med.ub.es/MIMMUN/FORUM/CAPS.HTM), and it is expected that the periodical analysis of these data will allow us to increase our knowledge of this condition.
European Forum on Antiphospholipid Antibodies: research in progress
Authors: Meroni PL , Tincani A , Alarcón-Riquelme ME , Shoenfeld Y , Borghi MO
Published: August 2009

The research projects of the European Forum on Antiphospholipid Antibodies are representative of how dynamic is this area of investigation. The present review is focused on the most recent projects of the Forum on the aetiopathogenic aspects of the antiphospholipid syndrome (APS). Studies on the genetic background of the APS are ongoing in order to better define the proximity between APS and full-blown systemic lupus erythematosus. However, the analysis of the polymorphisms of genes coding for inflammatory mediators may offer new information on the role of inflammatory processes in triggering thrombotic events as well as the whole susceptibility for developing the vascular manifestations. A systematic and wide detection of serological markers of infectious processes will give new insight on the role of infectious agents in favouring autoimmunity in APS. Owing to the well-known role of vitamin D3 defect in autoimmune disease, the detection of vitamin plasma levels in APS patients will offer the rationale for a possible therapeutic supplementation. Additional projects are aimed to better characterize the diagnostic/prognostic value of antiphospholipid antibodies (aPL) by defining their epitope specificity and binding avidity. Pregnancy complications represent the obstetric side of APS. Research projects are focussed on the role of complement activation in placenta damage and on the potential ability of aPL to affect the fertility. Finally, a study has been planned in order to draw definitive conclusions on the associations between aPL and atherosclerosis.
The Ped-APS Registry: the antiphospholipid syndrome in childhood
Authors: Avčin T , Cimaz R , Rozman B ,   The Ped-APS Registry Collaborative Group*
Published: August 2009

In recent years, antiphospholipid syndrome (APS) has been increasingly recognised in various paediatric autoimmune and nonautoimmune diseases, but the relatively low prevalence and heterogeneity of APS in childhood made it very difficult to study in a systematic way. The project of an international registry of paediatric patients with APS (the Ped-APS Registry) was initiated in 2004 to foster and conduct multicentre, controlled studies with large number of paediatric APS patients. The Ped-APS Registry is organised as a collaborative project of the European Forum on Antiphospholipid Antibodies and Juvenile Systemic Lupus Erythematosus Working Group of the Paediatric Rheumatology European Society. Currently, it documents a standardised clinical, laboratory and therapeutic data of 133 children with antiphospholipid antibodies (aPL)-related thrombosis from 14 countries. The priority projects for future research of the Ped-APS Registry include prospective enrolment of new patients with aPL-related thrombosis, assessment of differences between the paediatric and adult APS, evaluation of proinflammatory genotype as a risk factor for APS manifestations in childhood and evaluation of patients with isolated nonthrombotic aPL-related manifestations.
Immunogenetic studies on systemic lupus erythematosus
Authors: Sebastiani GD , Galeazzi M
Published: August 2009

Understanding the pathogenesis of systemic lupus erythematosus (SLE) remains a considerable challenge. Multiple abnormalities of both the innate and adaptive immune system have been described and, furthermore, immunological dysfunction precedes clinical presentation by many years. There is a strong genetic basis to SLE, which means that genetic studies can play a key role in furthering our understanding of this disease. Because susceptibility variants are present from birth and are unaffected by the course of the disease, or by its treatment, genetic analysis is, perhaps uniquely, capable of identifying fundamental, causative, disease mechanisms. In this article, we review our SLE immunogenetic studies performed in collaboration with the European Working Party on Systemic Lupus Erythematosus. By considering the results of our research and the recent advances obtained by genome-wide associations’ studies, we can begin to understand how dysregulation at a number of key immunological steps may predispose to the development of SLE.
Cancer Patients’ Perceptions of the Good Nurse: a Literature Review
Authors: Rchaidia Leila , Dierckx de Casterlé Bernadette , De Blaeser Liesbeth , Gastmans Chris
Published: August 2009

This article discusses findings from a mixed method literature review that investigated cancer patients’ perceptions of what constitutes a good nurse. To find pertinent articles, we conducted a systematic key word search of five journal databases (1998—2008). The application of carefully constructed inclusion criteria and critical appraisal identified 12 relevant articles. According to the patients, good nurses were shown to be characterized by specific, but inter-related, attitudes, skills and knowledge; they engage in person-to-person relationships, respect the uniqueness of patients, and provide support. Professional and trained skills as well as broad and specific nursing and non-nursing knowledge are important. The analysis revealed that these characteristics nurtured patient well-being, which manifests as optimism, trust, hope, support, confirmation, safety and comfort. Cancer patients’ perceptions of what constitutes a good nurse represent an important source of knowledge that will enable the development of more comprehensive and practice-based views on good nursing care for such patients. These perceptions help us to understand how nurses effectively make a difference in cancer patient care.
Hospitalized Children’s vIews of the Good Nurse
Authors: Brady Mary
Published: August 2009

Research relating to patients’ views of the good nurse has mainly focused on the perspectives of adult patients, with little exploring the perceptions of children. This article presents findings from a qualitative study that explored views of the good nurse from the perspective of hospitalized children. The aims of the study were threefold: to remedy a gap in the literature; to identify characteristics of the good nurse from the perspective of children in hospital; and to inform children’s nursing practice. Twenty-two children were interviewed using an adapted ‘draw and write’ technique. Five themes relating to children’s views of the good nurse emerged from the analysis: communication; professional competence; safety; professional appearance; and virtues. Each of these will be discussed in relation to good nurse literature and recommendations made for children’s nursing practice.
Municipal Night Nurses’ Experience of the Meaning of Caring
Authors: Gustafsson Christine , Asp Margareta , Fagerberg Ingegerd
Published: August 2009

The aim of this study was to elucidate municipal night registered nurses’ (RNs) experiences of the meaning of caring in nursing. The research context involved all night duty RNs working in municipal care of older people in a medium-sized municipality located in central Sweden. The meaning of caring in nursing was experienced as: caring for by advocacy, superior responsibility in caring, and consultative nursing service. The municipal night RNs’ experience of caring is interpreted as meanings in paradoxes: ‘being close at distance’, the condition of ‘being responsible with insignificant control’, and ‘being interdependently independent’. The RNs’ experience of the meaning of caring involves focusing on the care recipient by advocating their perspectives. The meaning of caring in this context is an endeavour to grasp an overall caring responsibility by responding to vocational and personal demands regarding the issue of being a RN, in guaranteeing ethical, qualitative and competent care for older people.
The Importance of Time in Ethical Decision Making
Authors: Monteverde Settimio
Published: August 2009

Departing from a contemporary novel about a boy who is going to die from leukaemia, this article shows how the dimension of time can be seen as a morally relevant category that bridges both ‘dramatic’ issues, which constitute the dominant focus of bioethical decision making, and ‘undramatic’ issues, which characterize the lived experience of patients, relatives and health care workers. The moral task of comparing the various time dimensions of a given situation is explained as an act of ‘synchronizing’ the clocks. Ethical sensitivity and competence are presented as core skills that allow a continuity of care in situations where dramatic issues seem to be resolved, but undramatic ones are still not addressed. A nine-step model of shared decision making is proposed as an approach to identifying critical junctures within an illness trajectory and synchronizing the clocks of the involved actors.
The Japanese Value of Harmony and Nursing Ethics
Authors: Konishi Emiko , Yahiro Michiko , Nakajima Naoko , Ono Miki
Published: August 2009

Harmony is one of the most fundamental Japanese values. It is derived from Confucianism and encompasses a state of mind, an action process and outcomes of the action. This article draws on research data and discusses Japanese nurses’ perceptions of harmony as reflected in their everyday practice. The most important virtues for these nurses were reported as politeness and respect for other persons. The outcome from the nurses’ harmonious practice, it is claimed, benefited patients and created peaceful, harmonious relationships for all. Because of the unique link between harmony and the location of interaction, the ideal ‘workplace harmony’ threatened some nurses’ professional decision making. These nurses confused harmony with conformity by superficial agreement. The Japanese seniority system could be a major factor contributing to this problem. Ethics education that includes traditional values and concepts in Japanese culture is strongly urged.
HER-2 Protein Overexpressing Breast Cancer Without Gene Amplification Shows Higher Hormone Receptor Expression Than HER-2 Protein Overexpressing Breast Cancer With Gene Amplification
Authors: Koo Ja Seung , Jung Woohee , Yang Woo Ick
Published: August 2009

Cases of breast cancer showing human epidermal growth factor receptor-2 (HER-2) protein overexpression without corresponding gene amplification have been found in immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) results. We investigated the clinicopathological characteristics of cases showing HER-2 protein overexpression breast cancer without gene amplification (IHC3+/FISH−) and compared them to cases showing HER-2 protein overexpression breast cancer with gene amplification (IHC3+/FISH+). This study was conducted on 90 patients with HER-2 IHC3+ breast cancer. The clinicopathological factors analyzed included tumor size, histological grade, nuclear grade, nodal involvement, and hormone receptor status. HER-2 IHC3+/FISH− breast cancer was found in 14 of 84 tumors (16.7%) and showed a statistically significant lower histological and nuclear grade ( P = .000) and higher expression of estrogen receptors (ERs) and progesterone receptors (PRs) ( P = .006) than IHC3+/FISH+ breast cancer. In conclusion, HER-2 IHC3+/FISH− breast cancer could be a subgroup showing lower histological/nuclear grade and higher expression of ERs/PRs.
Vascular and Capsular Pseudoinvasion in Thyroid Neoplasms
Authors: Chebib Ivan , Opher Elana , Richardson Mark E.
Published: August 2009

The diagnosis of follicular carcinoma of the thyroid requires the identification of capsular and/or vascular invasion, with the exception of distant metastases. However, several artifacts may mimic both vascular and capsular invasion. This article presents two cases of pseudo invasion in encapsulated follicular neoplasms. Their differentiation from true vascular and capsular invasion is discussed and the criteria for true invasion are reviewed.
Sclerosing Angiomatoid Nodular Transformation (SANT) of the Spleen: A Report of 3 Cases
Authors: Koreishi Aashiyana F. , Saenz Adam J. , Fleming Stephen E. , Teruya-Feldstein Julie
Published: August 2009

The authors describe 3 cases of sclerosing angiomatoid nodular transformation (SANT) of the spleen diagnosed at Memorial Sloan-Kettering Cancer Center within a 1-year period (July 2008 to June 2009). All patients were female, older than 50, with lesions ranging in size from 2 to 4 cm. All were alive and well after splenectomy. All the cases showed characteristic histological and immunophenotypical findings as previously described in the literature, including scattered IgG4positive plasma cells in the fibrosclerotic stroma. Of the 3 patients, 2 had a history of carcinoma, and metastasis was of concern, but a PET scan in one of these patients showed minimal to absent FDG activity suggesting that this process was of a benign indolent nature. However, in 1 patient, a PET scan revealed positive FDG activity, heightening clinical concern for malignancy.
Brooding and Pondering
Authors: Armey Michael F. , Fresco David M. , Moore Michael T. , Mennin Douglas S. , Turk Cynthia L. , Heimberg Richard G. , Kecmanovic Jelena , Alloy Lauren B.
Published: August 2009

Depressive rumination, as assessed by Nolen-Hoeksema’s Response Styles Questionnaire (RSQ), predicts the onset, chronicity, and duration of depressed mood. However, some RSQ items contain depressive content and result in a heterogeneous factor structure. After the a priori elimination of items potentially confounded with depressed item content, Treynor, Gonzalez, and Nolen-Hoeksema identified two factors within the remaining RSQ rumination sub-scale that were differentially related to depression: brooding and pondering. However, Treynor et al. used a nonstandard form and administration of the RSQ. The present study sought to address these methodological idiosyncrasies and replicate the factor structure of Treynor et al. through exploratory factor analysis and structural equation modeling. Findings support the brooding and pondering solution and demonstrate that brooding relates more strongly to depression and anxiety than does pondering.
Perioperative Pain, Psychological Distress, and Immune Function in Men Undergoing Prostatectomy for Cancer of the Prostate
Authors: Yermal Stephen J. , Witek-Janusek Linda , Peterson Jonna , Mathews Herbert L.
Published: August 2009

Prostate cancer is a leading malignancy in men, and prostatectomy is widely used for its treatment. Psychological distress and pain are commonly experienced in the perioperative period, and both can contribute to suppression of the immune response to cancer. This study evaluated perioperative pain, psychological distress, and immune function in men undergoing prostatectomy. Men were evaluated prior to surgery, 1 and 2 days postoperatively and 4—6 weeks postoperatively. Compared to cancer-free men, the prostatectomy group reported increased perceived stress, depression, confusion, and anxiety prior to surgery. During the 2 postoperative days, mood disturbance and anxiety persisted and were accompanied by mild elevations in pain and reduced vigor. At 4—6 weeks postoperative, mood, pain, and immune function were similar to those of the cancer-free group; however, the prostatectomy group continued to report significant elevations in anxiety. Natural killer cell activity (NKCA) was significantly reduced on Day 1 after prostatectomy, but by postoperative Day 2, NKCA returned to a level similar to that of the cancer-free group. The reduction in NKCA was not accompanied by changes in circulating immune cells, demonstrating that this reduction represented a functional change in NKCA. No correlations between immune variables and pain or psychological variables were found, suggesting that the postoperative reduction in NKCA was likely the result of the physical stress of the surgical experience. Suppression of immune defenses during the critical postoperative period can place cancer patients at risk for nascent tumor seeding. Additional interventions are needed to reduce this risk.
Walking and talking: an investigation of cognitive—motor dual tasking in multiple sclerosis
Authors: Hamilton F. , Rochester L. , Paul L. , Rafferty D. , O'Leary CP , Evans JJ
Published: August 2009

Background: Deficits in motor functioning, including walking, and in cognitive functions, including attention, are known to be prevalent in multiple sclerosis (MS), though little attention has been paid to how impairments in these areas of functioning interact.

Objectives: This study investigated the effects of performing a concurrent cognitive task when walking in people with MS. Level of task demand was manipulated to investigate whether this affected level of dual-task decrement.

Method: Eighteen participants with MS and 18 healthy controls took part. Participants completed walking and cognitive tasks under single- and dual-task conditions.

Results: Compared to healthy controls, MS participants showed greater decrements in performance under dual-task conditions in cognitive task performance, walking speed and swing time variability. In the MS group, the degree of decrement under dual-task conditions was related to levels of fatigue, a measure of general cognitive functioning and self-reported everyday cognitive errors, but not to measures of disease severity or duration.

Conclusions: Difficulty with walking and talking in MS may be a result of a divided attention deficit or of overloading of the working memory system, and further investigation is needed. We suggest that difficulty with walking and talking in MS may lead to practical problems in everyday life, including potentially increasing the risk of falls. Clinical tools to assess cognitive—motor dual-tasking ability are needed.
Antiacquaporin 4 antibodies detection by different techniques in neuromyelitis optica patients
Authors: Fazio R. , Malosio ML , Lampasona V. , De Feo D. , Privitera D. , Marnetto F. , Centonze D. , Ghezzi A. , Comi G. , Furlan R. , Martino G.
Published: August 2009

Background: Antibodies against aquaporin-4 (AQP4), a water channel particularly expressed on perivascular astrocytic podocytes, are proposed as a marker for the diagnosis of neuromyelitis optica (NMO). However, a consensus on seroprevalence and optimal detection method has not yet been reached.

Objectives: To investigate the performance of different assays to detect anti-AQP4 antibodies.

Methods: We set up five different assays. Two of them were capable to detect perivascular IgG reactivity on brain tissue by immunofluorescence (NMO-IgG). Other three assays have been set to detect anti-AQP4 antibodies: immunofluorescence and flow cytometry on AQP4-expressing cells, and a radioimmunoprecipitation assay. We assessed sensitivity and specificity of these assays by interrogating sera of 33 NMO patients, 13 patients at high risk to develop NMO (hrNMO), 6 patients affected by acute partial transverse myelitis (APTM), 20 patients with multiple sclerosis (MS), and 67 age- and sex-matched healthy controls.

Results: We found that the presence of serum NMO-IgG and anti-AQP4 reactivity is almost exclusively restricted to patients with NMO and hrNMO. Seroprevalence and sensitivity ranged from 30 to 47%, depending on the assay. Specificity ranged from 95 to 100%. Comparing results obtained in the five assays, we noticed lack of concordance in some samples.

Conclusions: Detection of NMO-IgG or anti-AQP4 antibodies may represent a valuable tool to assist neurologists in the differential diagnosis between patients with NMO, hrNMO, APTM, or MS. The current lack of a gold standard to detect anti-AQP4 antibodies implies the necessity to standardize the detection of these antibodies.
The marine environment and its influence on seafaring and maritime routes in the prehistoric Aegean
Authors: Papageorgiou Despoina
Published: August 2009

This article seeks to illustrate the decisive contribution of the sea environment and particularly the sea-surface circulation (which is determined by the circulation of sea currents and the winds) to the early growth of seafaring and maritime communications in the prehistoric Aegean. Given the means and techniques of navigation in that era, an attempt is made to reveal a dense network of sea routes which vessels could follow through the Aegean, in order to facilitate their trip. These sea routes are primarily based on environmental data and are confirmed concurrently by archaeological evidence and data of ancient sources. Therefore, it is evident that these sea routes played an important role not only in the early inhabitation of the Aegean islands and the foundation of coastal settlements throughout the Aegean area from the sixth millennium BC to the end of the third millennium BC, but in the development of the Aegean civilization during earlier prehistoric times as well.
Attitudes of Patients and Care Providers Toward a Surgical Site Marking Policy
Authors: Goldberg Amanda E. , Harnish Julie L. , Stegienko Stacey , Urbach David R.
Published: August 2009

Background: In the fall of 2005, the University Health Network in Toronto, Canada, initiated a policy requiring the surgeon-or his or her delegate-to sign the incision site for all operations. Little is known about what health care providers and patients think about official surgical site marking policy. Method: Twenty-one patients and health care providers were interviewed, and the authors conducted field observations of surgeons while they marked their patients. The data were analyzed using grounded theory methods. Findings: Surgical site marking was perceived to be a safety precaution for operations involving multiple sides and structures but not for cases where there is no uncertainty about the intended operative site. Participants believed that marking could also facilitate error if the wrong side was marked. Site marking was perceived to have the effect of ensuring that the surgeon meets with the patient prior to the operation on the day of surgery. Concerns were raised with respect to who should mark patients and marking surgical sites for genital surgery or other private body sites. Conclusions: For operations that involve multiple possible surgical sites, site marking should be carried out by individuals who are knowledgeable about the patient and the proposed procedure. For operations in which there is no uncertainty about the intended site, interventions other than site marking could be implemented to ensure patient-surgeon interactions on the day of surgery. Surgical site marking procedures should respect patient dignity and privacy.
Self-reported chronic mental health problems and mental health service use in Spain
Authors: Girón Manuel , Nolasco Andreu , Pereyra-Zamora Pamela , Munarriz Mikel , Salazar José , Tabarés Rafael , Moncho-Vasallo Joaquín , Gómez-Beneyto Manuel
Published: August 2009

Objectives: To determine the prevalence of self-reported chronic mental health problems (MHPs) and mental health service use and their determinants, among the Spanish population over 14 years of age.

Methods: Data from the 1999 Spanish Survey on Disabilities, Deficiencies, and State of Health were used. The survey is a cross-sectional study based on a multi-stage stratified sample of all the non-institutionalized Spanish population aged over 14 years (n=59,101, 11% non-responders). Multivariate logistic regression analysis were used.

Results: 10.7% of the Spanish population suffer from an MHP. The highest prevalences were found in women, divorced/separated persons, those with a lower level of education and income, and those suffering from a chronic somatic problem. The number of days of daily activity lost was 2-fold greater among those with an MHP than among those with a chronic somatic problem. Greater use of mental health services was associated with loss of daily activity, having a higher level of education, invalidity or disability. The probability of MHP being referred from primary to mental healthcare is reduced if somatic comorbidity is present.

Conclusion: MHPs have a high prevalence and a significant repercussion on the patient’s life. An inverse relationship was found between certain risk factors for MHPs and the use of services, which suggests inequality. Problems of accessibility are identified.
Teaching and learning about chronic conditions management for undergraduate medical students: utilizing the patient-as-teacher approach
Authors: McKinlay E. , McBain L. , Gray B.
Published: August 2009

Objectives: This study was undertaken to evaluate the impact on medical student learning of a revised chronic conditions teaching programme based on the chronic care model utilizing patients-as-teachers.

Methods: A qualitative questionnaire was completed by students at the start of a primary healthcare rotation to determine existing impressions/understandings about chronic conditions. Following the revised teaching programme, a reflective essay about a home-visit to a person with chronic conditions was completed by students at the end of the rotation.

Results: Analysis of the questionnaire at the start of the rotation showed students have some knowledge of the differences between acute and chronic care, have rather negative impressions of what it means to have chronic conditions and know little of overall patient management including the work of an interdisciplinary team. Analysis of the reflective essays completed by students at the end of the rotation showed an increased understanding of chronic conditions, what it means to have a chronic condition and who supports management.

Discussion: A structured chronic conditions teaching programme including patient-as-teacher is an effective way of building knowledge and changing students’ impressions of what it means to have a chronic condition.
Tight control of MEK-ERK activation is essential in regulating proliferation, survival, and cytokine production of CD34+-derived neutrophil progenitors
Authors: Geest Christian R. , Buitenhuis Miranda , Groot Koerkamp Marian J. A. , Holstege Frank C. P. , Vellenga Edo , Coffer Paul J.
Published: August 2009

A plethora of extracellular stimuli regulate growth, survival, and differentiation responses through activation of the MEK-ERK MAPK signaling module. Using CD34+ hematopoietic progenitor cells, we describe a novel role for the MEK-ERK signaling module in the regulation of proliferation, survival, and cytokine production during neutrophil differentiation. Addition of the specific MEK1/2 inhibitor U0126 resulted in decreased proliferation of neutrophil progenitors. Conversely, transient activation of a conditionally active MEK1 mutant resulted in the expansion of progenitor cells, which thereafter differentiated normally into mature neutrophils. In contrast, chronic MEK1 activation was found to induce cell death of CD34+ neutrophil progenitors. Microarray analysis of CD34+ progenitor cells showed that activation of MEK1 resulted in changes in expression of a variety of cell-cycle modulating genes. Furthermore, conditional activation of MEK1 resulted in a dramatic increase in the expression of mRNA transcripts encoding a large number of hematopoietic cytokines, chemokines, and growth factors. These findings identify a novel role for MEK-ERK signaling in regulating the balance between proliferation and apoptosis during neutrophil differentiation, and they suggest the need for tight control of MEK-ERK activation to prevent the development of bone marrow failure.
A novel role for c-Src and STAT3 in apoptotic cell–mediated MerTK-dependent immunoregulation of dendritic cells
Authors: Yi Zuoan , Li Li , Matsushima Glenn K. , Earp H. Shelton , Wang Bo , Tisch Roland
Published: August 2009

Dendritic cells (DCs) play an instrumental role in regulating tolerance to self-antigens and preventing autoimmunity. One mechanism by which “tolerogenic” DCs are established is through the inhibitory effects of apoptotic cells (ACs). Immature DCs encountering ACs are resistant to stimuli that activate and mature DCs. We have shown that the Mer receptor tyrosine kinase (MerTK) plays a key role in transducing inhibitory signals upon binding of ACs, which in turn involve the phosphatidylinositol 3-kinase (PI3K) pathway. Nevertheless, the molecular basis for AC-induced inhibition of DCs is ill defined. In the current study, the proximal signaling events induced by MerTK after AC binding were studied. AC treatment of bone marrow–derived or splenic DCs established a complex consisting of MerTK, the nonreceptor tyrosine kinase c-Src, the transcription factor STAT3, and PI3K. In contrast, AC treatment of DCs lacking MerTK expression failed to increase c-Src and STAT3 activation. In addition, the inhibitory effects of ACs were blocked by treating DCs with pharmacologic inhibitors or siRNA specific for c-Src and STAT3. These findings demonstrate that AC-induced inhibition of DCs requires MerTK-dependent activation of c-Src and STAT3, and provide evidence for novel roles for c-Src and STAT3 in the immunoregulation of DCs.
Efficient and stable transduction of resting B lymphocytes and primary chronic lymphocyte leukemia cells using measles virus gp displaying lentiviral vectors
Authors: Frecha Cecilia , Costa Caroline , Lévy Camille , Nègre Didier , Russell Stephen J. , Maisner Andrea , Salles Gilles , Peng Kah-Whye , Cosset Francois-Loïc , Verhoeyen Els
Published: August 2009

Up to now, no lentiviral vector (LV) tool existed to govern efficient and stable gene delivery into quiescent B lymphocytes, which hampers its application in gene therapy and immunotherapy areas. Here, we report that LVs incorporating measles virus (MV) glycoproteins, H and F, on their surface allowed transduction of 50% of quiescent B cells, which are not permissive to VSVG-LV transduction. This high transduction level correlated with B-cell SLAM expression and was not at cost of cell-cycle entry or B-cell activation. Moreover, the naive and memory phenotypes of transduced resting B cells were maintained. Importantly, H/F-LVs represent the first tool permitting stable transduction of leukemic cancer cells, B-cell chronic lymphocytic leukemia cells, blocked in G0/G1 early phase of the cell cycle. Thus, H/F-LV transduction overcomes the limitations of current LVs by making B cell–based gene therapy and immunotherapy applications feasible. These new LVs will facilitate antibody production and the study of gene functions in these healthy and cancer immune cells.
Level and course of FEV1 in relation to polymorphisms in NFE2L2 and KEAP1 in the general population
Authors: Siedlinski Mateusz , Postma Dirkje S , Boer Jolanda MA , van der Steege Gerrit , Schouten Jan P , Smit Henriette A , Boezen H Marike
Published: August 2009

Background

The metabolism of xenobiotics plays an essential role in smoking related lung function loss and development of Chronic Obstructive Pulmonary Disease. Nuclear Factor Erythroid 2-Like 2 (NFE2L2 or NRF2) and its cytosolic repressor Kelch-like ECH-associated protein-1 (KEAP1) regulate transcription of enzymes involved in cellular detoxification processes and Nfe2l2-deficient mice develop tobacco-induced emphysema. We assessed the impact of Single Nucleotide Polymorphisms (SNPs) in both genes on the level and longitudinal course of Forced Expiratory Volume in 1 second (FEV1) in the general population.

Methods

Five NFE2L2 and three KEAP1 tagging SNPs were genotyped in the population-based Doetinchem cohort (n = 1,152) and the independent Vlagtwedde-Vlaardingen cohort (n = 1,390). On average 3 FEV1 measurements during 3 surveys, respectively 7 FEV1 measurements during 8 surveys were present. Linear Mixed Effect models were used to test cross-sectional and longitudinal genetic effects on repeated FEV1 measurements.

Results

In the Vlagtwedde-Vlaardingen cohort SNP rs11085735 in KEAP1 was associated with a higher FEV1 level (p = 0.02 for an additive effect), and SNP rs2364723 in NFE2L2 was associated with a lower FEV1 level (p = 0.06). The associations were even more significant in the pooled cohort analysis. No significant association of KEAP1 or NFE2L2 SNPs with FEV1 decline was observed.

Conclusion

This is the first genetic study on variations in key antioxidant transcriptional regulators KEAP1 and NFE2L2 and lung function in a general population. It identified 2 SNPs in NFE2L2 and KEAP1 which affect the level of FEV1 in the general population. It additionally shows that NFE2L2 and KEAP1 variations are unlikely to play a role in the longitudinal course of FEV1 in the general population.
Gain and loss of an intron in a protein-coding gene in Archaea: the case of an archaeal RNA pseudouridine synthase gene
Authors: Yokobori Shin-ichi , Itoh Takashi , Yoshinari Shigeo , Nomura Norimichi , Sako Yoshihiko , Yamagishi Akihiko , Oshima Tairo , Kita Kiyoshi , Watanabe Yoh-ichi
Published: August 2009

Background

We previously found the first examples of splicing of archaeal pre-mRNAs for homologs of the eukaryotic CBF5 protein (also known as dyskerin in humans) inAeropyrum pernix, Sulfolobus solfataricus, S. tokodaii, andS. acidocaldarirus, and also showed that crenarchaeal species in orders Desulfurococcales and Sulfolobales, except forHyperthermus butylicus, Pyrodictium occultum, Pyrolobus fumarii, andIgnicoccus islandicus, contain the (putative)cbf5intron. However, the exact timing of the intron insertion was not determined and verification of the putative secondary loss of the intron in some lineages was not performed.

Results

In the present study, we determined approximately two-thirds of the entire coding region of crenarchaeal Cbf5 sequences from 43 species. A phylogenetic analysis of our data and information from the available genome sequences suggested that the (putative)cbf5intron existed in the common ancestor of the orders Desulfurococcales and Sulfolobales and that probably at least two independent lineages in the order Desulfurococcales lost the (putative) intron.

Conclusion

This finding is the first observation of a lineage-specific loss of a pre-mRNA intron in Archaea. As the insertion or deletion of introns in protein-coding genes in Archaea has not yet been seriously considered, our finding suggests the possible difficulty of accurately and completely predicting protein-coding genes in Archaea.
Combined genome-wide expression profiling and targeted RNA interference in primary mouse macrophages reveals perturbation of transcriptional networks associated with interferon signalling
Authors: Lacaze Paul , Raza Sobia , Sing Garwin , Page David , Forster Thorsten , Storm Petter , Craigon Marie , Awad Tarif , Ghazal Peter , Freeman Tom C
Published: August 2009

Background

Interferons (IFNs) are potent antiviral cytokines capable of reprogramming the macrophage phenotype through the induction of interferon-stimulated genes (ISGs). Here we have used targeted RNA interference to suppress the expression of a number of key genes associated with IFN signalling in murine macrophages prior to stimulation with interferon-gamma. Genome-wide changes in transcript abundance caused by siRNA activity were measured using exon-level microarrays in the presence or absence of IFNγ.

Results

Transfection of murine bone-marrow derived macrophages (BMDMs) with a non-targeting (control) siRNA and 11 sequence-specific siRNAs was performed using a cationic lipid transfection reagent (Lipofectamine2000) prior to stimulation with IFNγ. Total RNA was harvested from cells and gene expression measured on Affymetrix GeneChip Mouse Exon 1.0 ST Arrays. Network-based analysis of these data revealed six siRNAs to cause a marked shift in the macrophage transcriptome in the presence or absence IFNγ. These six siRNAs targeted the Ifnb1, Irf3, Irf5, Stat1, Stat2 and Nfkb2 transcripts. The perturbation of the transcriptome by the six siRNAs was highly similar in each case and affected the expression of over 600 downstream transcripts. Regulated transcripts were clustered based on co-expression into five major groups corresponding to transcriptional networks associated with the type I and II IFN response, cell cycle regulation, and NF-KB signalling. In addition we have observed a significant non-specific immune stimulation of cells transfected with siRNA using Lipofectamine2000, suggesting use of this reagent in BMDMs, even at low concentrations, is enough to induce a type I IFN response.

Conclusion

Our results provide evidence that the type I IFN response in murine BMDMs is dependent on Ifnb1, Irf3, Irf5, Stat1, Stat2 and Nfkb2, and that siRNAs targeted to these genes results in perturbation of key transcriptional networks associated with type I and type II IFN signalling and a suppression of macrophage M1 polarization.
Rapid identification of bacterial pathogens using a PCR- and microarray-based assay
Authors: Järvinen Anna-Kaarina , Laakso Sanna , Piiparinen Pasi , Aittakorpi Anne , Lindfors Merja , Huopaniemi Laura , Piiparinen Heli , Mäki Minna
Published: August 2009

Background

During the course of a bacterial infection, the rapid identification of the causative agent(s) is necessary for the determination of effective treatment options. We have developed a method based on a modified broad-range PCR and an oligonucleotide microarray for the simultaneous detection and identification of 12 bacterial pathogens at the species level. The broad-range PCR primer mixture was designed using conserved regions of the bacterial topoisomerase genes gyrB and parE. The primer design allowed the use of a novel DNA amplification method, which produced labeled, single-stranded DNA suitable for microarray hybridization. The probes on the microarray were designed from the alignments of species- or genus-specific variable regions of the gyrB and parE genes flanked by the primers. We included mecA-specific primers and probes in the same assay to indicate the presence of methicillin resistance in the bacterial species. The feasibility of this assay in routine diagnostic testing was evaluated using 146 blood culture positive and 40 blood culture negative samples.

Results

Comparison of our results with those of a conventional culture-based method revealed a sensitivity of 96% (initial sensitivity of 82%) and specificity of 98%. Furthermore, only one cross-reaction was observed upon investigating 102 culture isolates from 70 untargeted bacteria. The total assay time was only three hours, including the time required for the DNA extraction, PCR and microarray steps in sequence.

Conclusion

The assay rapidly provides reliable data, which can guide optimal antimicrobial treatment decisions in a timely manner.
Black race as a predictor of poor health outcomes among a national cohort of HIV/AIDS patients admitted to US hospitals: a cohort study
Authors: Oramasionwu Christine U , Hunter Jonathan M , Skinner Jeff , Ryan Laurajo , Lawson Kenneth A , Brown Carolyn M , Makos Brittany R , Frei Christopher R
Published: August 2009

Background

In general, the Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) population has begun to experience the benefits of highly active antiretroviral therapy (HAART); unfortunately, these benefits have not extended equally to Blacks in the United States, possibly due to differences in patient comorbidities and demographics. These differences include rates of hepatitis B and C infection, substance use, and socioeconomic status. To investigate the impact of these factors, we compared hospital mortality and length of stay (LOS) between Blacks and Whites with HIV/AIDS while adjusting for differences in these key characteristics.

Methods

The 1996–2006 National Hospital Discharge Surveys were used to identify HIV/AIDS patients admitted to US hospitals. Survey weights were incorporated to provide national estimates. Patients < 18 years of age, those who left against medical advice, those with an unknown discharge disposition and those with a LOS < 1 day were excluded. Patients were stratified into subgroups by race (Black or White). Two multivariable logistic regression models were constructed with race as the independent variable and outcomes (mortality and LOS > 10 days) as the dependent variables. Factors that were significantly different between Blacks and Whites at baseline via bivariable statistical tests were included as covariates.

Results

In the general US population, there are approximately 5 times fewer Blacks than Whites. In the present study, 1.5 million HIV/AIDS hospital discharges were identified and Blacks were 6 times more likely to be hospitalized than Whites. Notably, Blacks had higher rates of substance use (30% vs. 24%; P < 0.001), opportunistic infections (27% vs. 26%; P < 0.001) and cocaine use (13% vs. 5%; P < 0.001). Conversely, fewer Blacks were co-infected with hepatitis C virus (8% vs. 12%; P < 0.001). Hepatitis B virus was relatively infrequent (3% for both groups). Crude mortality rates were similar for both cohorts (5%); however, a greater proportion of Blacks had a LOS > 10 days (21% vs. 19%; P < 0.001). Black race, in the presence of comorbidities, was correlated with a higher odds of LOS > 10 days (OR, 95% CI = 1.20 [1.10–1.30]), but was not significantly correlated with a higher odds of mortality (OR, 95% CI = 1.07 [0.93–1.25]).

Conclusion

Black race is a predictor of LOS > 10 days, but not mortality, among HIV/AIDS patients admitted to US hospitals. It is possible that racial disparities in hospital outcomes may be closing with time.
Neck/shoulder pain in adolescents is not related to the level or nature of self-reported physical activity or type of sedentary activity in an Australian pregnancy cohort
Authors: Briggs Andrew M , Straker Leon M , Bear Natasha L , Smith Anne J
Published: August 2009

Background

An inconsistent relationship between physical activity and neck/shoulder pain (NSP) in adolescents has been reported in the literature. Earlier studies may be limited by not assessing physical activity in sufficient detail. The aim of this study was to comprehensively examine the association between NSP and the level and nature of physical activity, and type of sedentary activity in adolescents.

Methods

A cross-sectional analysis using data from 924 adolescents in the Western Australian Pregnancy Cohort (RAINE) study was performed. Complete data were available for 643 adolescents (54.6% female) at the 14-year follow-up. Physical activity was measured using a detailed self-report electronic activity diary requiring participants to input details of all physical activities over the day in segments of 5 minutes for a one-week period. Physical activity levels were categorised as: sedentary, light, moderate, or vigorous based on metabolic energy equivalents. Nature of activity was determined by assigning each activity to categories based on the amount of movement (static/dynamic) and the main posture assumed for the activity (standing/sitting/lying). Type of sedentary activity was characterised by exposure time to watching TV, using a computer, and reading. Logistic regression was used to explore the association between NSP and activity.

Results

Females reported a higher prevalence of lifetime, 1-month and chronic NSP than males (50.9 vs 41.7%, 34.1 vs 23.5%, and 9.2 vs 6.2% respectively). No consistent, dose-response relationship was found between NSP and the level, nature, and type of physical activity.

Conclusion

Self-reported one month and lifetime NSP prevalence in adolescents is not related to the level or intensity of physical activity or the type of sedentary activity over a one week period.
Malaria has no effect on birth weight in Rwanda
Authors: Rulisa Stephen , Mens Pètra F , Karema Corine , Schallig Henk DFH , Kaligirwa Nadine , Vyankandondera Joseph , de Vries Peter J
Published: August 2009

Background

Malaria has a negative effect on pregnancy outcome, causing low birth weight, premature birth and stillbirths, particularly in areas with high malaria transmission. In Rwanda, malaria transmission intensity ranges from high to nil, probably associated with variable altitudes. Overall, the incidence decreased over the last six years (2002–2007). Therefore, the impact of malaria on birth outcomes is also expected to vary over time and space.

Methods

Obstetric indicators (birth weight and pregnancy outcome) and malaria incidence were compared and analyzed to their association over time (2002–2007) and space. Birth data from 12,526 deliveries were collected from maternity registers of 11 different primary health centers located in different malaria endemic areas. Malaria data for the same communities were collected from the National Malaria Control Programme. Associations were sought with mixed effects models and logistic regression.

Results

In all health centres, a significant increase of birth weight over the years was observed (p < 0.001) with a significant seasonal fluctuation. Malaria incidence had no significant effect on birth weight. There was a slight but significant decreasing effect of malaria incidence on the occurrence of premature delivery (p-value 0.045) and still birth (p-value 0.009). Altitude showed a slight but significant negative correlation with birth weight. Overall, a decrease over the years of premature delivery (p = 0.010) and still birth (p = 0.036) was observed.

Conclusion

In Rwanda, birth weight and pregnancy outcome are not directly influenced by malaria, which is in contrast to many other studied areas. Although malaria incidence overall has declined and mean birth weight increased over the studied period, no direct association was found between the two. Socio-economic factors and improved nutrition could be responsible for birth weight changes in recent years.