bluuebunny/crossref_metadata_2025 huggingface dataset:
The Responsibility to Protect: A Legal and Rights-based Perspective
Authors: Gierycz Dorota
Published: July 2010

This article analyses the responsibility to protect from a legal and rights-based perspective. It shows that the responsibility to protect populations from genocide, war crimes, ethnic cleansing and crimes against humanity is rooted in existing International Human Rights Law (IHRL) and International Humanitarian Law (IHL). These crimes fall under the jurisdiction of the International Criminal Court (ICC) and evoke serious international legal consequences under all circumstances, also if tried by national courts. Protection of the individual against atrocities is a primary responsibility of states. However, if a state is unable or unwilling to exercise its protection obligations, these shift to international organisations, including the United Nations or any other authority controlling the territory and its population. The article further analyses various protection tools available within the UN human rights machinery, in particular the Human Rights Council (HRC) and the Office of the High Commissioner for Human Rights (OHCHR) and concludes that they could play a much stronger role in preventing and addressing the atrocities and that the most important obstacle in this respect is the prevailing institutional gap between human rights and security matters within the UN. The article concludes that the responsibility to protect clause adopted by consensus by the 2005 World Summit in its Outcome Document (GA Resolution A/60/1) constitutes an important commitment towards implementing these universal rights and obligations which are lacking enforcement and continue to be violated, especially in armed conflicts. It also identifies research and policy recommendations that may facilitate operationalisation of this important clause.
Analysis of a Two-Level Structural Equation Model With Missing Data
Authors: Poon Wai-Yin , Wang Hai-Bin
Published: July 2010

Structural equation models are widely used to model relationships among latent unobservable constructs and observable variables. In some studies, the data set used for analysis is comprised of observations that are drawn from a known hierarchical structure and involves missing entries. A two-level structural equation model can be used to analyze such data sets. Direct maximum likelihood methods for analyzing two-level structural equation models are available in software, such as LISREL and Mplus. These software programs also have options to handle missing observations. The authors develop an alternative procedure that uses an expectation maximization (EM) type algorithm. Using appropriate approximations, the procedure can be implemented using simple statistical software in combination with a basic structural equation modeling program. The authors address the implementation of the procedure in detail and provide syntax codes in R, which is available in the public domain, to implement the proposed procedure. The discussion of the procedure is made with reference to the analysis of a data set that studies job characteristic variables. The authors also use simulation studies to examine the performance of the proposed procedure. The results indicate that the proposed method, which is easily accessible to users, represents a reliable alternative for analyzing two-level structural equation models with missing data.
Does Low‐Dose Heparin Maintain Central Venous Access Device Patency?
Authors: Jonker Mark A. , Osterby Kurt R. , Vermeulen Lee C. , Kleppin Susan M. , Kudsk Kenneth A.
Published: July 2010

Background: A common problem that complicates use of central venous access devices (CVADs) is occlusion by thrombosis. Alteplase, a recombinant tissue plasminogen activator, is used to restore line patency when thrombosis occurs. Heparin flush is commonly used to prevent this complication, but the effectiveness of this practice is unclear. A recent heparin shortage allowed examination of heparin effectiveness in reducing CVAD thrombosis. Methods: A retrospective cohort study was performed by querying a pharmacy database for alteplase use for CVAD thrombosis in adult patients during periods when heparin flushes (10 units/mL) were used and when saline flushes were used instead because of a nationwide heparin shortage. The number of patients receiving alteplase, the number of doses administered, and the total amount of alteplase used were compared over 1‐month intervals of heparin flush use and 1‐month intervals of saline flush use. Patient days and critical care patient days were compared between these time intervals. Peripherally inserted central catheter (PICC) line placements and replacements between time periods of heparin and saline flush were also compared. Results: Significant increases in the number of patients receiving alteplase (P = .04), the number of alteplase doses administered (P = .04), and total dose of alteplase used (P = .05) occurred during the heparin shortage. No significant differences in patient population were observed. The percentage of PICC line replacements also increased significantly (P < .05) when heparin was not available. Conclusions: Heparin flush (10 units/mL) decreases thrombotic occlusions of CVADs, resulting in decreased alteplase use and fewer PICC line replacements.
Fluoroscopy‐Guided Percutaneous Gastrostomy With Pull Technique for the Amyotrophic Lateral Sclerosis Patients With Very Low Vital Capacity
Authors: Park Jung Hyun , Kang Seong‐Woong , Won Jong Yun , Uhm Chang Wook
Published: July 2010

Background: The purpose of this study was to evaluate the safety and usefulness of fluoroscopy‐guided percutaneous gastrostomy (FPG) in patients with amyotrophic lateral sclerosis (ALS) using a large‐profile gastrostomy tube accompanied by the pull technique. This procedure was done without an accompanying endoscopy or gastropexy. Methods: Thirty‐six patients with ALS underwent FPG using a large‐profile gastrostomy tube accompanied by the pull technique. A 24 Fr pull‐type tube was inserted under fluoroscopic guidance into the mouth and pulled to the upper‐abdominal puncture site using a snare. The technical success rate, occurrence of complications, and clinical outcomes were evaluated. Results: The technical success rate was 100%. There were no procedure‐related mortalities or respiratory complications. The mean forced vital capacity of the patients was 732 mL (17.7% of the normal predicted value). During the procedure, 16 patients required ventilator support by nasal mask or tracheostomy. The tube indwelling period ranged from 1 to 24 months (average, 9.3). During this period, all the tubes were maintained in a proper position. In 18 patients, the tube was exchanged after 6 months without any problems. Conclusions: The FPG procedure using a 24 Fr tube and the pull technique shows a high rate of technical success. This procedure has a low risk for respiratory complications because endoscopic guidance is not needed. In addition, gastropexy is not required, which allows a large‐profile catheter to be inserted during a single procedure.
Early Fish Oil Supplementation and Organ Failure in Patients With Septic Shock From Abdominal Infections
Authors: Wohlmuth Christoph , Dünser Martin W. , Wurzinger Bettina , Deutinger Martina , Ulmer Hanno , Torgersen Christian , Schmittinger Christian A. , Grander Wilhelm , Hasibeder Walter R.
Published: July 2010

Background: Fish oil (FO) has immunomodulating effects and may improve organ function and outcome in critically ill patients. This retrospective, propensity‐matched cohort study investigates the effects of early intravenous FO supplementation on organ failure in patients with septic shock from abdominal infection. Methods: A medical database was retrospectively searched for critically ill patients admitted because of septic shock from abdominal infection (n = 194). Demographic, clinical, and laboratory data; FO supplementation (10 g/d) (n = 42); rate, degree, and number of organ failures assessed by the Sequential Organ Failure Assessment (SOFA) score; and secondary outcome variables were recorded. A propensity score‐based model was used to establish 2 comparable groups (FO, n = 29; control, n = 29). Mann‐Whitney rank sum test, Fisher exact test, and logistic regression analyses were used to compare variables between groups. Results: There were no differences in the rate of single organ failures, the maximum SOFA score (median [interquartile range (IQR)], 12 [8‐15] vs 11 [9‐14]; P = .99), or the number of organ failures (median [IQR], 2 [1‐3] vs 2 [1‐3]; P = .54] between patients receiving FO supplementation and those not receiving supplementation. There were no group differences in the maximum C‐reactive protein levels (P = .1), duration of mechanical ventilation (P = .65) or hemofiltration (P = .21), intensive care unit–acquired infections, intensive care unit length of stay (P = .59), and intensive care unit (P = 1) or hospital mortality (P = 1). Conclusions: Early intravenous FO may not decrease the number and degree of organ failures in patients with septic shock from abdominal infection. Future trials are needed before FO supplementation in septic shock from abdominal infection can be recommended.
Reconstructing scale: Towards a new scalar politics
Authors: MacKinnon Danny
Published: July 2010

In recent years, the dominant political-economic approach to scale has been subject to critique from poststructuralist perspectives. In this paper, I argue that the charge of ‘reification’ has been accepted too readily, masking areas of conceptual overlap between political-economic and poststructural approaches, particularly in terms of their shared concern with the construction of scale. On this basis, I propose to replace the established concept of ‘the politics of scale’ with ‘scalar politics’, arguing that it is often not scale per se that is the prime object of contention, but rather specific processes and institutionalized practices that are themselves differentially scaled.
Human geography and the institutions that underlie economic growth
Authors: Farole Thomas , Rodríguez-Pose Andrés , Storper Michael
Published: July 2010

Human geography is in a unique position to understand how local structural factors shape social, political, and ultimately economic outcomes. Indeed, the discipline has had much to say about the interaction between local institutions and the economy in general, and about how the broader institutions of society influence local economic development. Yet, to date, geographers have for the most part avoided debates on more generalized theories of economic growth and development. With the increasing recognition — among sociologists, political scientists and even economists — that explaining economic growth robustly requires taking into account the role of both formal society-wide institutions and local and sometimes informal institutions, geographers are in a position to make an important contribution. In order to do so, however, they will need to take greater account of the theories and developments that are taking place outside the discipline. Using the framework of community and society as complementary structural forces shaping development trajectories, this paper presents a broad overview of the principal theoretical and empirical developments in the institutionalist approaches to economic development and identifies areas in which geographical research could contribute to them.
Mutational Analysis of the MECP2 Gene in Tunisian Patients With Rett Syndrome: A Novel Double Mutation
Authors: Fendri-Kriaa Nourhene , Mkaouar-Rebai Emna , Moalla Dorsaf , Belguith Neila , Louhichi Nacim , Zemni Ramzi , Slama Foued , Triki Chahnez , Fakhfakh Faiza ,   Tunisian Network on Mental Retardation
Published: July 2010

Rett syndrome is a severe disorder characterized by loss of acquired skills after a period of normal development in infant girls. It is caused mainly by mutations in the MECP2 gene. In this study, we reported mutations in the MECP2 gene in 7 Tunisian patients with classic Rett syndrome. The results showed the presence of a double mutation in 1 patient: p.R306C and c.1461+98insA, which create a new hypothetical polyadenylation site in the 3′UTR of the MECP2 gene. We also detected in another patient a new variant c.1461+92C>G in the 3′UTR located previous to 34 bp from the polyadenylation site with a score of 4.085. This variation is located in a hypothetical splicing enhancer with a score of 1.96277 according to the ESE finder program. In the remaining 5 patients, we found 2 common mutations: p.T158M in 4 individuals and p.R168X in only 1 girl.
Decadal-scale rainfall variability in Ethiopia recorded in an annually laminated, Holocene-age, stalagmite
Authors: Baker Andy , Asrat Asfawossen , Fairchild Ian J. , Leng Melanie J. , Thomas Louise , Widmann Martin , Jex Catherine N. , Buwen Dong  , van Calsteren Peter , Bryant Charlotte
Published: July 2010

An annually laminated, uranium-series dated, Holocene stalagmite from southeast Ethiopia has been analysed for growth rate and δ13C and δ18O variations at annual to biennial resolution, in order to provide the first long duration proxy record of decadal-scale rainfall variability in this climatically sensitive region. Our study site (10°N) is climatically influenced by both summer (June—August) and spring (March—May) rainfall caused by the annual movement of the Inter-Tropical Convergence Zone (ITCZ) and modulated by large-scale anomalies in the atmospheric circulation and in ocean temperatures. Here we show that stalagmite growth, episodic throughout the last 7800 years, demonstrates decadal-scale (8—25 yr) variability in both growth rate and δ 18O. A hydrological model was employed and indicates that this decadal variability is due to variations in the relative amounts of rainfall in the two rain seasons. Our record, unique in its combination of length (a total of ~1000 years), annual chronology and high resolution δ18O, shows for the first time that such decadal-scale variability in rainfall in this region has occurred through the Holocene, which implies persistent decadal-scale variability for the large-scale atmospheric and oceanic driving factors.
The Authoritarian Reign in American Health Care
Authors: Ballou Kathryn A. , Landreneau Kandace J.
Published: July 2010

The aim of this article is to increase understanding of the mechanisms of the continuation of elite hegemonic control of a highly valued social system—American health care. White, male physicians and administrators achieved control of the health care industry and its workers, including nurses, at the start of the 20th century. Using critical theorists’ work on authoritarianism and incorporating gender analysis, the authors describe the health care system from a critical social— psychological perspective. The authors discuss the meaning and presence of authoritarian hierarchy and gender effects in today’s health system through a critical analysis of the profession of medicine, the profession of nursing, corporate and bureaucratic health care, and patients or consumers. It is concluded that the social—psychological behavior of the American health care system has profound implications that must be taken into account in any recommendations for change.
A Noval Approach Using Angioplasty for Recanalization of a Chronically Occluded Bypass Vein Graft for Limb Salvage
Authors: Slim Hani , Huang Dean , Rashid Hisham
Published: July 2010

Background: Reporting a noval approach for recanalization of a chronically occluded bypass using balloon angioplasty. Methods: A chronically occluded distal bypass graft was managed successfully with balloon angioplasty in a diabetic patient with critically ischemic leg. Results: Successful recanalization of the chronically occluded distal bypass graft. Surveillance duplex scans up to 10 months revealed the graft to be patent with pulsatile flow. Patient fully healed. Conclusion: Balloon angioplasty of a chronically occluded distal bypass is feasible.
Nurse religiosity and end-of-life care
Authors: Bjarnason Dana
Published: July 2010

Much has been written about nurses’ responsibility to support patients’ spiritual needs. A plethora of literature explores patients’ religiosity and its effect on their approach and/or response to healthcare issues. There is little literature exploring the influence of healthcare providers’ religiosity on the care they deliver to patients. This research examines the relationship between nurses’ religiosity, their perceived self-efficacy, and the importance they place on aspects of care provided to patients at the end of life. This study further supports the body of literature suggesting that end-of-life care is complex and multidimensional. It presents findings that show significant relationships between religiosity, self-efficacy, and the importance that nurses report regarding end-of-life care, and demonstrates the need for ongoing research that investigates aspects of nursing and end-of-life care.
Bioreconstructive Poly-L/D-Lactide Implant Compared With Swanson Prosthesis in Metacarpophalangeal Joint Arthroplasty in Rheumatoid Patients: a Randomized Clinical Trial
Authors: Honkanen P.B. , Thonen R. , Skyttä E.T. , Ikävalko M. , Lehto M.U.K. , Konttinen Y.T.
Published: July 2010

It was hypothesized that the bioresorbable interposition implant might offer a viable alternative to conventional silicone implant arthroplasty in rheumatoid metacarpophalangeal joint destruction. A randomized clinical study was performed to compare a stemless poly-L/D-lactide copolymer 96: 4 (PLDLA) implant with the Swanson silicone implant. Results in 52 patients (53 hands and 175 joints) at a mean follow-up of 2 years (minimum 1 year) showed that the improvement in clinical assessments was comparable in both groups, except for better maintenance of palmar alignment in the Swanson group. The lack of implant fractures and intramedullary osteolysis were advantages of the PLDLA implant. The bioresorbable PLDLA interposition implant may offer an alternative tool for tailored reconstruction of rheumatoid metacarpophalangeal joints.
Acute exacerbation of chronic obstructive pulmonary disease in primary care setting in Spain: the EPOCAP study
Authors: Murio Cristina , Soler Xavier , Pérez Maite , Calero Gabriel , Ruiz-Manzano Juan
Published: July 2010

Background: The present study was designed to describe the clinical profile of acute exacerbations of chronic obstructive pulmonary disease (COPD) and the treatment prescribed by primary care physicians (PCPs) in Spain.

Method: An observational, multicenter and cross-sectional study was performed in patients diagnosed with acute exacerbation of COPD and treated by PCPs. Patients diagnosed with asthma, cystic fibrosis, significant bronchiectasis or pneumonia were not included in the study.

Results: A total of 329 general physicians recruited 1088 evaluable patients across the country. Mean age was 66.5±10.2 years; male : female ratio was 3 : 1. Spirometry was performed in 28.3% of the patients. The number of acute exacerbations in the last year was 3.3±2.5; 88.7% had increased expectoration, 87.5% increased dyspnea, 64.4% increased sputum purulence, and 43.5% fever. A total of 6.1% ( n = 59) of patients were hospitalized due to exacerbation. The most frequently prescribed medications were antibiotics (84.5%, n = 919), mucolytic agents (72.5%, n = 789), inhaled corticosteroids (ICs) (71.3%, n = 776), and short-acting beta-adrenergic drugs (67.8%, n = 738). Oral corticosteroids were prescribed to 436 patients (40.1%).

Conclusions: The clinical profile of acute exacerbations of COPD treated in a primary care setting in Spain was characterized by shortness of breath and increased sputum production. Patients were managed by PCP mainly in outpatient clinics with antibiotics, mucolytic agents, inhaled corticosteroids, oral corticosteroids and short-acting beta-adrenergic agents. The percentage of patients with confirmed diagnosis of COPD by pulmonary function tests was very low.
Renal Hemodynamic Changes Assessed by Color Doppler Sonography in Children With Liver Cirrhosis
Authors: Abufaddan Nagla Hassan , Omar Nagham Nabeel
Published: July 2010

Detection of early renal affection before proceeding to hepatorenal failure as a complication of liver cirrhosis in children will be helpful in the prognosis of the disease. The objective of this study was to detect early hemodynamic changes in children with liver cirrhosis who had normal kidney function tests to measure the pulsatility index (PI) and resistance index (RI) and their correlation to some risk factors (severity of cirrhosis, renal infection, blood hemoglobin level, and the presence of portal hypertension). Thirty children with different stages of liver cirrhosis (with normal kidney function tests) and 10 apparently healthy children were included. RI and PI were measured by Doppler spectral wave analysis for patients and control. Both PI and RI indices were significantly higher in all children with liver cirrhosis compared with the control group. Both indices showed highest values with class C compared with classes B and A. Each was significantly higher in the presence of anemia, renal infection and portal hypertension. Monitoring of resistance indices (PI and RI) measured noninvasively by Doppler sonography is an effective and easy method for detection of very early renal hemodynamic alternation in childhood cirrhosis and consequently early proper management.
The impact of anti-HLA antibodies on unrelated cord blood transplantations
Authors: Takanashi Minoko , Atsuta Yoshiko , Fujiwara Koki , Kodo Hideki , Kai Shunro , Sato Hiroyuki , Kohsaki Masatoshi , Azuma Hiroshi , Tanaka Hidenori , Ogawa Atsuko , Nakajima Kazunori , Kato Shunichi
Published: July 2010

The majority of cord blood transplantations (CBTs) have human leukocyte antigen (HLA) disparities. We investigated the impact that patients' pretransplantation anti-HLA antibodies have on the outcome of CBTs. Testing for anti-HLA antibody and its specificity was performed retrospectively at the Japanese Red Cross Tokyo Blood Center with sensitive solid-phase antibody detection assays. Among 386 CBTs, which were first myeloablative stem cell transplantations for malignancies and used a single unit of cord blood, 89 tested positive. Among the antibody-positive group, the cord blood did not have the corresponding HLA type for the antibody in 69 cases (ab-positive), while 20 cases had specificity against the cord blood HLA (positive-vs-CB). Cumulative incidence of neutrophil recovery 60 days after transplantation was 83% (95% confidence interval [CI], 79%-87%) for the antibody-negative group (ab-negative), 73% (95% CI, 61%-82%) for ab-positive, but only 32% (95% CI, 13%-53%) for the positive-vs-CB (P < .0001, Gray test). With multivariate analysis, the ab-positive showed significantly lower neutrophil recovery than the ab-negative (relative risk [RR] = 0.69, 95% CI, 0.49-0.96, p = .027). The positive-vs-CB had significantly lower neutrophil recovery (RR = 0.23, 95% CI, 0.09-0.56, P = .001) and platelet recovery (RR = 0.31, 95% CI, 0.12-0.81, P = .017) than the ab-negative. Patients' pretransplantation anti-HLA antibodies should be tested and considered in the selection of cord blood.
Adoptive transfer of pp65-specific T cells for the treatment of chemorefractory cytomegalovirus disease or reactivation after haploidentical and matched unrelated stem cell transplantation
Authors: Feuchtinger Tobias , Opherk Kathrin , Bethge Wolfgang A. , Topp Max S. , Schuster Friedhelm R. , Weissinger Eva M. , Mohty Mohamad , Or Reuven , Maschan Michael , Schumm Michael , Hamprecht Klaus , Handgretinger Rupert , Lang Peter , Einsele Hermann
Published: July 2010

Cytomegalovirus (CMV) disease and infection refractory to antiviral treatment after allogeneic stem cell transplantation (allo-SCT) is associated with a high mortality. Adoptive transfer of CMV-specific T cells could reconstitute viral im-munity after SCT and could protect from CMV-related complications. However, logistics of producing virus-specific T-cell grafts limited the clinical application. We treated 18 patients after allo-SCT from human leukocyte antigen–mismatched/haploidentical or human leukocyte antigen–matched unrelated donors with polyclonal CMV-specific T cells generated by ex vivo stimulation with pp65, followed by isolation of interferon-γ–producing cells. Patients with CMV disease or viremia refractory to antiviral chemotherapy or both were eligible for adoptive T-cell transfer and received a mean of 21 × 103/kg pp65-specific T cells. In 83% of cases CMV infection was cleared or viral burden was significantly reduced, even in cases of CMV encephalitis (n = 2). Viral control was associated with in vivo expansion of CMV-specific T lymphocytes in 12 of 16 evaluable cases, resulting in reconstitution of antiviral T-cell responses, without graft-versus-host disease induction or acute side effects. Our findings indicate that the infusion of low numbers of CMV-specific T cells is safe, feasible, and effective as a treatment on demand for refractory CMV infection and CMV disease after allo-SCT.
Hepatic HIF-2 regulates erythropoietic responses to hypoxia in renal anemia
Authors: Kapitsinou Pinelopi P. , Liu Qingdu , Unger Travis L. , Rha Jennifer , Davidoff Olena , Keith Brian , Epstein Jonathan A. , Moores Sheri L. , Erickson-Miller Connie L. , Haase Volker H.
Published: July 2010

The kidney is the main physiologic source of erythropoietin (EPO) in the adult and responds to decreases in tissue oxygenation with increased EPO production. Although studies in mice with liver-specific or global gene inactivation have shown that hypoxia-inducible factor 2 (Hif-2) plays a major role in the regulation of Epo during infancy and in the adult, respectively, the contribution of renal HIF-2 signaling to systemic EPO homeostasis and the role of extrarenal HIF-2 in erythropoiesis, in the absence of kidney EPO, have not been examined directly. Here, we used Cre-loxP recombination to ablate Hif-2α in the kidney, whereas Hif-2–mediated hypoxia responses in the liver and other Epo-producing tissues remained intact. We found that the hypoxic induction of renal Epo is completely Hif-2 dependent and that, in the absence of renal Hif-2, hepatic Hif-2 takes over as the main regulator of serum Epo levels. Furthermore, we provide evidence that hepatocyte-derived Hif-2 is involved in the regulation of iron metabolism genes, supporting a role for HIF-2 in the coordination of EPO synthesis with iron homeostasis.
Effect of parity on fetal and maternal microchimerism: interaction of grafts within a host?
Authors: Gammill Hilary S. , Guthrie Katherine A. , Aydelotte Tessa M. , Waldorf Kristina M. Adams , Nelson J. Lee
Published: July 2010

Small amounts of genetically foreign cells (microchimerism, Mc) traffic between a mother and fetus during pregnancy. Commonly, these grafts durably persist. For women, multiple naturally acquired Mc grafts can accrue, as they harbor Mc from their own mothers (maternal Mc, MMc) and subsequently acquire fetal Mc (FMc) through pregnancy. The nature of interactions between these naturally acquired grafts may inform, and be informed by, observations in transplantation, including the effect of noninherited maternal HLA antigens (NIMA) and double-unit cord blood transplantation (CBT). We asked whether FMc and MMc are impacted by the addition of new grafts as evaluated by increasing parity. Mc was identified by quantitative PCR for a nonshared polymorphism unique to the Mc source. Despite increasing sources of Mc, FMc did not increase with increasing parity. MMc concentration was significantly lower with increasing parity. The odds ratio for detection of MMc for 2 or more births compared with 1 birth was .11 (95% CI 0.03-0.42, P = .001). These observations suggest that interactions occur among naturally acquired grafts and are of interest in light of recent observations of graft-graft interaction resulting in predominance of 1 unit in double-unit CBT and the correlation of MMc with the NIMA effect.
Superior outcomes associated with complete response in newly diagnosed multiple myeloma patients treated with nonintensive therapy: analysis of the phase 3 VISTA study of bortezomib plus melphalan-prednisone versus melphalan-prednisone
Authors: Harousseau Jean-Luc , Palumbo Antonio , Richardson Paul G. , Schlag Rudolf , Dimopoulos Meletios A. , Shpilberg Ofer , Kropff Martin , Kentos Alain , Cavo Michele , Golenkov Anatoly , Komarnicki Mieczyslaw , Mateos Maria-Victoria , Esseltine Dixie-Lee , Cakana Andrew , Liu Kevin , Deraedt William , van de Velde Helgi , San Miguel Jesús F.
Published: July 2010

The phase 3 Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment with Melphalan and Prednisone study in newly diagnosed multiple myeloma patients ineligible for high-dose therapy demonstrated that bortezomib-melphalan-prednisone (VMP) was superior to melphalan-prednisone across all efficacy end points. We assessed the prognostic impact of response on time-to-event parameters in the intent-to-treat population. Patients received nine 6-week cycles of treatment. Time to progression, time to next therapy, and treatment-free interval were associated with quality of response. When European Group for Blood and Marrow Transplantation criteria were used, complete response (CR) was associated with significantly longer time to progression (hazard ratio [HR] = 0.45, P = .004), time to next therapy (HR = 0.46, P = .0004), and treatment-free interval (HR = 0.38, P < .0001) versus partial response, but there was no significant difference in overall survival (HR = 0.87, P = .54); similar differences were seen with CR versus very good partial response by uniform criteria. Quality of response improved with prolonged VMP treatment, with 28% of CRs achieved during cycles 5-9. CR duration appeared similar among patients with “early” (cycles 1-4) and “late” CRs (cycles 5-9) and among patients receiving 9 versus < 9 cycles of bortezomib within VMP. These results highlight that CR is an important treatment goal and support prolonged VMP therapy to achieve maximal response. This study is registered at http://www.clinicaltrials.gov as NCT00111319.
Association between red blood cell transfusions and development of non-Hodgkin lymphoma: a meta-analysis of observational studies
Authors: Castillo Jorge J. , Dalia Samir , Pascual Sheila K.
Published: July 2010

The incidence of non-Hodgkin lymphoma (NHL) has increased steadily for the past few decades. Previous studies have suggested an association between blood transfusions and NHL. The main objective of this study was to evaluate this relationship with a meta-analysis of observational studies. A literature search was undertaken, looking for case-control and cohort studies evaluating the risk of developing NHL in persons who received allogeneic blood transfusions; 14 studies were included. Outcome was calculated and reported as relative risk (RR). Heterogeneity was assessed with Cochrane Q and I2 statistics. Dissemination bias was evaluated by funnel plot visualization and trim-and-fill analysis. Quality assessment was performed with the Newcastle-Ottawa scale. Our analysis showed a RR of developing NHL of 1.05 (95% CI, 0.89-1.25; P = .42) and 1.34 (95% CI, 1.15-1.55; P < .01) in case-control and cohort studies, respectively. When pooling all studies, RR was 1.2 (95% CI, 1.07-1.35; P < .01). In subset analysis, RR of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) was 1.66 (95% CI, 1.08-2.56; P = .02). The RR of NHL was elevated in both men and women and in persons receiving transfusions either before or after 1992. Blood transfusions appear to increase the risk of developing NHL; however, the risk of CLL/SLL appears higher than for other NHL subtypes.
The first trimester human placenta is a site for terminal maturation of primitive erythroid cells
Authors: Van Handel Ben , Prashad Sacha L. , Hassanzadeh-Kiabi Nargess , Huang Andy , Magnusson Mattias , Atanassova Boriana , Chen Angela , Hamalainen Eija I. , Mikkola Hanna K. A.
Published: July 2010

Embryonic hematopoiesis starts via the generation of primitive red blood cells (RBCs) that satisfy the embryo's immediate oxygen needs. Although primitive RBCs were thought to retain their nuclei, recent studies have shown that primitive RBCs in mice enucleate in the fetal liver. It has been unknown whether human primitive RBCs enucleate, and what hematopoietic site might support this process. Our data indicate that the terminal maturation and enucleation of human primitive RBCs occurs in first trimester placental villi. Extravascular ζ-globin+ primitive erythroid cells were found in placental villi between 5-7 weeks of development, at which time the frequency of enucleated RBCs was higher in the villous stroma than in circulation. RBC enucleation was further evidenced by the presence of primitive reticulocytes and pyrenocytes (ejected RBC nuclei) in the placenta. Extravascular RBCs were found to associate with placental macrophages, which contained ingested nuclei. Clonogenic macrophage progenitors of fetal origin were present in the chorionic plate of the placenta before the onset of fetoplacental circulation, after which macrophages had migrated to the villi. These findings indicate that placental macrophages may assist the enucleation process of primitive RBCs in placental villi, implying an unexpectedly broad role for the placenta in embryonic hematopoiesis.
In vitro and in vivo targeted delivery of IL-10 interfering RNA by JC virus-like particles
Authors: Chou Meng-Ing , Hsieh Yu-Fan , Wang Meilin , Chang Jinghua Tsai , Chang Deching , Zouali Moncef , Tsay Gregory J
Published: July 2010

Background

RNA interference (RNAi) is a powerful tool to silence gene expression post-transcriptionally. Delivering sequences of RNAi in vivo remains a problem. The aim of this study was to use JC virus (JCV) virus-like particles (VLPs) as a vector for delivering RNAi in silencing the cytokine gene of IL-10.

Methods

JCV VLPs were generated by recombinant JCV VP1 protein in yeast expression system. DNA fragment containing IL-10 shRNA was packaged into VLPs by osmotic shock.

Results

In RAW 264.7 cells, IL-10 shRNA was found to reduce IL-10 expression by 85 to 89%, as compared with VLPs alone. IL-10 shRNA did not cross-react with TNF-alpha mRNA or influence the expression of TNF-alpha. In BALB/c mice IL-10 shRNA could reduce 95% of IL-10 secretion. Surprisingly, it also down regulated TNF-alpha expression.

Conclusions

We show for the first time that JCV VLPs empty capsids are competent vectors to deliver RNAi and are nontoxic to cells, suggesting that JCV VLPs is an efficient agent to deliver RNAi in both murine macrophage cells and BALB/c mice. This system provides an efficient means for delivering the RNAi for gene therapy purposes.
Increasing the amylose content of durum wheat through silencing of the SBEIIagenes
Authors: Sestili Francesco , Janni Michela , Doherty Angela , Botticella Ermelinda , D'Ovidio Renato , Masci Stefania , Jones Huw D , Lafiandra Domenico
Published: July 2010

Background

High amylose starch has attracted particular interest because of its correlation with the amount of Resistant Starch (RS) in food. RS plays a role similar to fibre with beneficial effects for human health, providing protection from several diseases such as colon cancer, diabetes, obesity, osteoporosis and cardiovascular diseases. Amylose content can be modified by a targeted manipulation of the starch biosynthetic pathway. In particular, the inactivation of the enzymes involved in amylopectin synthesis can lead to the increase of amylose content. In this work, genes encoding starch branching enzymes of class II (SBEIIa) were silenced using the RNA interference (RNAi) technique in two cultivars of durum wheat, using two different methods of transformation (biolistic and Agrobacterium). Expression of RNAi transcripts was targeted to the seed endosperm using a tissue-specific promoter.

Results

Amylose content was markedly increased in the durum wheat transgenic lines exhibiting SBEIIa gene silencing. Moreover the starch granules in these lines were deformed, possessing an irregular and deflated shape and being smaller than those present in the untransformed controls. Two novel granule bound proteins, identified by SDS-PAGE in SBEIIa RNAi lines, were investigated by mass spectrometry and shown to have strong homologies to the waxy proteins. RVA analysis showed new pasting properties associated with high amylose lines in comparison with untransformed controls. Finally, pleiotropic effects on other starch genes were found by semi-quantitative and Real-Time reverse transcription-polymerase chain reaction (RT-PCR).

Conclusion

We have found that the silencing of SBEIIa genes in durum wheat causes obvious alterations in granule morphology and starch composition, leading to high amylose wheat. Results obtained with two different methods of transformation and in two durum wheat cultivars were comparable.
Anti-apoptotic role of HIF-1 and AP-1 in paclitaxel exposed breast cancer cells under hypoxia
Authors: Flamant Lionel , Notte Annick , Ninane Noelle , Raes Martine , Michiels Carine
Published: July 2010

Background

Hypoxia is a hallmark of solid tumors and is associated with metastases, therapeutic resistance and poor patient survival.

Results

In this study, we showed that hypoxia protected MDA-MB-231 breast cancer cells against paclitaxel- but not epirubicin-induced apoptosis. The possible implication of HIF-1 and AP-1 in the hypoxia-induced anti-apoptotic pathway was investigated by the use of specific siRNA. Specific inhibition of the expression of these two transcription factors was shown to increase apoptosis induced by chemotherapeutic agents under hypoxia indicating an involvement of HIF-1 and AP-1 in the anti-apoptotic effect of hypoxia. After HIF-1 specific inhibition and using TaqMan Human Apoptosis Array, 8 potential HIF-1 target genes were identified which could take part in this protection. Furthermore, Mcl-1 was shown to be a potential AP-1 target gene which could also participate to the hypoxia-induced chemoresistance.

Conclusions

Altogether, these data highlight two mechanisms by which hypoxia could mediate its protective role via the activation of two transcription factors and, consecutively, changes in gene expression encoding different anti- and pro-apoptotic proteins.
Echocardiography of isolated subacute left heart tamponade in a patient with cor pulmonale and circumferential pericardial effusion
Authors: Marš Tomaž , Mikolavčič Helena , Salobir Barbara , Podbregar Matej
Published: July 2010

Patients with advanced idiopathic pulmonary artery hypertension have often a chronic pericardial effusion. It is the result of increased transudation and impaired re-absorption due to elevated venous pressure. These patients have pre-existent symptoms and signs of chronic right heart failure. High degree of suspicion is required to detect of development of an atypical form of tamponade with isolated compression of left heart chambers as shown in present case report. Transthoracic echocardiography provides a rapid access to the correct diagnosis, a prompt relief of symptoms following the ultrasound guided pericardiocentesis and important diagnostic tool for regular follow up of patients thereafter as shown in our case report.
IgG transmitted from allergic mothers decreases allergic sensitization in breastfed offspring
Authors: Matson Adam P , Thrall Roger S , Rafti Ektor , Lingenheld Elizabeth G , Puddington Lynn
Published: July 2010

Background

The mechanism(s) responsible for the reduced risk of allergic disease in breastfed infants are not fully understood. Using an established murine model of asthma, we demonstrated previously that resistance to allergic airway disease transmitted from allergic mothers to breastfed offspring requires maternal B cell-derived factors.

Objective

The aim of this study was to investigate the role of offspring neonatal Fc receptor for IgG uptake by intestinal epithelial cells (FcRn) in this breast milk transferred protection from allergy.

Methods

Allergic airway disease was induced during pregnancy in C57BL/6 female mice. These allergic mothers foster nursed naive FcRn+/-or FcRn-/-progeny born to FcRn+/-females that were mated to C57BL/6J-FcRn-/-male mice. In offspring deficient in FcRn, we expected reduced levels of systemic allergen-specific IgG1, a consequence of decreased absorption of maternal IgG from the lumen of the neonatal gastrointestinal tract. Using this model, we were able to investigate how breast milk IgG affected offspring responses to allergic sensitization.

Results

Levels of maternal antibodies absorbed from the breast milk of allergic foster mothers were determined in weanling FcRn-sufficient or -deficient mice. Maternal transmission of allergen-specific IgG1to breastfed FcRn-/-offspring was at levels 103-104lower than observed in FcRn+/-or FcRn+/+mice. Five weeks after weaning, when offspring were 8 wk old, mice were sensitized and challenged to evaluate their susceptibility to develop allergic airway disease. Protection, indicated by reduced parameters of disease (allergen-specific IgE in serum, eosinophilic inflammation in the airways and lung) were evident in FcRn-sufficient mice nursed as neonates by allergic mothers. In contrast, FcRn-deficient mice breastfed by the same mothers acquired limited, if any, protection from development of allergen-specific IgE and associated pathology.

Conclusions

FcRn expression was a major factor in determining how breastfed offspring of allergic mothers acquired levels of systemic allergen-specific IgG1sufficient to inhibit allergic sensitization in this model.
Concentration of acrylamide in a polyacrylamide gel affects VP4 gene coding assignment of group A equine rotavirus strains with P[12] specificity
Authors: Long-Croal LaShanda M , Wen Xiaobo , Ostlund Eileen N , Hoshino Yasutaka
Published: July 2010

Background

It is universally acknowledged that genome segment 4 of group A rotavirus, the major etiologic agent of severe diarrhea in infants and neonatal farm animals, encodes outer capsid neutralization and protective antigen VP4.

Results

To determine which genome segment of three group A equine rotavirus strains (H-2, FI-14 and FI-23) with P[12] specificity encodes the VP4, we analyzed dsRNAs of strains H-2, FI-14 and FI-23 as well as their reassortants by polyacrylamide gel electrophoresis (PAGE) at varying concentrations of acrylamide. The relative position of the VP4 gene of the three equine P[12] strains varied (either genome segment 3 or 4) depending upon the concentration of acrylamide. The VP4 gene bearing P[3], P[4], P[6], P[7], P[8] or P[18] specificity did not exhibit this phenomenon when the PAGE running conditions were varied.

Conclusions

The concentration of acrylamide in a PAGE gel affected VP4 gene coding assignment of equine rotavirus strains bearing P[12] specificity.
Hereditary combined deficiency of the vitamin K-dependent clotting factors
Authors: Napolitano Mariasanta , Mariani Guglielmo , Lapecorella Mario
Published: July 2010

Hereditary combined vitamin K-dependent clotting factors deficiency (VKCFD) is a rare congenital bleeding disorder resulting from variably decreased levels of coagulation factors II, VII, IX and X as well as natural anticoagulants protein C, protein S and protein Z. The spectrum of bleeding symptoms ranges from mild to severe with onset in the neonatal period in severe cases. The bleeding symptoms are often life-threatening, occur both spontaneously and in a surgical setting, and usually involve the skin and mucosae. A range of non-haemostatic symptoms are often present, including developmental and skeletal anomalies. VKCFD is an autosomal recessive disorder caused by mutations in the genes of either gamma-glutamyl carboxylase or vitamin K2,3-epoxide reductase complex. These two proteins are necessary for gamma-carboxylation, a post-synthetic modification that allows coagulation proteins to display their proper function. The developmental and skeletal anomalies seen in VKCFD are the result of defective gamma-carboxylation of a number of non-haemostatic proteins. Diagnostic differentiation from other conditions, both congenital and acquired, is mandatory and genotype analysis is needed to confirm the defect. Vitamin K administration is the mainstay of therapy in VKCFD, with plasma supplementation during surgery or severe bleeding episodes. In addition, prothrombin complex concentrates and combination therapy with recombinant activated FVII and vitamin K supplementation may constitute alternative treatment options. The overall prognosis is good and with the availability of several effective therapeutic options, VKCFD has only a small impact on the quality of life of affected patients.
Effect of duloxetine in patients with fibromyalgia: tiredness subgroups
Authors: Bradley Laurence A , Bennett Robert , Russell Irwin J , Wohlreich Madelaine M , Chappell Amy S , Wang Fujun , D'Souza Deborah N , Moldofsky Harvey
Published: July 2010

Introduction

This study tested the hypothesis that baseline ratings of fatigue/tiredness would be negatively associated with the efficacy of duloxetine on measures of pain and functional ability in patients with fibromyalgia.

Methods

A post hoc analysis of pooled data from 4 double-blind, placebo-controlled studies of duloxetine in fibromyalgia was performed. The fibromyalgia impact questionnaire (FIQ) tiredness item score (0 to 10 scale) was used to define tiredness subgroups. Patients were stratified into 3 subgroups: mild (0 to 3), moderate (4 to 6), and severe (7 to 10) tiredness. Analysis of covariance models and logistic regressions were used to test treatment-by-tiredness subgroup interactions.

Results

Data from the first 3 months are included in this post hoc analysis (duloxetine N = 797, placebo N = 535). At baseline, the distribution of tiredness severity in the duloxetine and placebo groups respectively was 3.64% and 3.75% mild, 16.71% and 15.57% moderate, and 79.65% and 80.68% severe. Rates of clinically significant (≥30% and ≥50%) improvement in brief pain inventory (BPI) average pain were similar across the tiredness subgroups. Tiredness severity at baseline was not negatively associated with the effects of duloxetine on patients' reports of functional ability using the FIQ total score, FIQ measures of physical impairment, interference with work, pain, stiffness, and depression and the medical outcomes study short form-36 (SF-36).

Conclusions

Studies of duloxetine in fibromyalgia have demonstrated clinically significant improvements in pain and functional ability (FIQ, SF-36). This post hoc analysis of data shows that the efficacy of duloxetine among patients with fibromyalgia does not vary as a function of baseline ratings of fatigue/tiredness.