bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hantavirus outbreak in Western Europe: reservoir host infection dynamics related to human disease patterns
Authors: TERSAGO K. , VERHAGEN R. , VAPALAHTI O. , HEYMAN P. , DUCOFFRE G. , LEIRS H. 
Published: May 2010

SUMMARYWithin Europe, Puumala virus (PUUV) is the causal agent of nephropathia epidemica (NE) in humans, a zoonotic disease with increasing significance in recent years. In a region of Belgium with a historically high incidence of NE, bank voles (the PUUV reservoir hosts), were monitored for PUUV IgG antibody prevalence in nine study sites before, during, and after the highest NE outbreak recorded in Belgium in 2005. We found that the highest numbers of PUUV IgG-positive voles coincided with the peak of NE cases at the regional level, indicating that a PUUV epizootic in bank voles directly led to the NE outbreak in humans. On a local scale, PUUV infection in voles was patchy and not correlated to NE incidence before the epizootic. However, during the epizootic period PUUV infection spread in the vole populations and was significantly correlated to local NE incidence. Initially, local bank-vole numbers were positively associated with local PUUV infection risk in voles, but this was no longer the case after the homogeneous spreading of PUUV during the PUUV outbreak.
Exponential integrators
Authors: Hochbruck Marlis , Ostermann Alexander 
Published: May 2010

In this paper we consider the construction, analysis, implementation and application of exponential integrators. The focus will be on two types of stiff problems. The first one is characterized by a Jacobian that possesses eigenvalues with large negative real parts. Parabolic partial differential equations and their spatial discretization are typical examples. The second class consists of highly oscillatory problems with purely imaginary eigenvalues of large modulus. Apart from motivating the construction of exponential integrators for various classes of problems, our main intention in this article is to present the mathematics behind these methods. We will derive error bounds that are independent of stiffness or highest frequencies in the system.Since the implementation of exponential integrators requires the evaluation of the product of a matrix function with a vector, we will briefly discuss some possible approaches as well. The paper concludes with some applications, in which exponential integrators are used.
Understanding waiting lists as the matching of surgical capacity to demand: are we wasting enough surgical time?
Authors: Pandit J. J. , Pandit M. , Reynard J. M. 
Published: May 2010

SummaryIf surgical ‘capacity’ always matched or exceeded ‘demand’ then there should be no waiting lists for surgery. However, understanding what is meant by ‘demand’, ‘capacity’ and ‘matched’ requires some mathematical concepts that we outline in this paper. ‘Time’ is the relevant measure: ‘demand’ for a surgical team is best understood as the total min required for the surgery booked from outpatient clinics every week; and ‘capacity’ is the weekly operating time available. We explain how the variation in demand (not just the mean demand) influences the analysis of optimum capacity. However, any capacity chosen in this way is associated with only a likelihood (that is, a probability rather than certainty) of absorbing the prevailing demand. A capacity that suitably absorbs the demand most of the time (for example, > 80% of weeks) will inevitably also involve considerable waste (that is, many weeks in which there is spare, unused capacity). Conversely, a level of capacity chosen to minimise wasted time will inevitably cause an increase in size of the waiting list. Thus the question of how to balance demand and capacity is intimately related to the question of how to balance utilisation and waste. These mathematical considerations enable us to consider objectively how to manage the waiting list. They also enable us critically to analyse the extent to which philosophies adopted by the National Health Service (such as ‘Lean’ or ‘Six Sigma’) will be successful in matching surgical capacity to demand.
A genome scan for quantitative trait loci influencing carcass, post‐natal growth and reproductive traits in commercial Angus cattle
Authors: McClure M. C. , Morsci N. S. , Schnabel R. D. , Kim J. W. , Yao P. , Rolf M. M. , McKay S. D. , Gregg S. J. , Chapple R. H. , Northcutt S. L. , Taylor J. F. 
Published: May 2010

SummaryTo gain insight into the number of loci of large effect that underlie variation in cattle, a quantitative trait locus (QTL) scan for 14 economically important traits was performed in two commercial Angus populations using 390 microsatellites, 11 single nucleotide polymorphisms (SNPs) and one duplication loci. The first population comprised 1769 registered Angus bulls born between 1955 and 2003, with Expected Progeny Differences computed by the American Angus Association. The second comprised 38 half‐sib families containing 1622 steers with six post‐natal growth and carcass phenotypes. Linkage analysis was performed by half‐sib least squares regression with gridqtl or Bayesian Markov chain Monte Carlo analysis of complex pedigrees with loki. Of the 673 detected QTL, only 118 have previously been reported, reflecting both the conservative approach to QTL reporting in the literature, and the more liberal approach taken in this study. From 33 to 71% of the genetic variance and 35 to 56% of the phenotypic variance in each trait was explained by the detected QTL. To analyse the effects of 11 SNPs and one duplication locus within candidate genes on each trait, a single marker analysis was performed by fitting an additive allele substitution model in both mapping populations. There were 53 associations detected between the SNP/duplication loci and traits with −log10Pnominal≥ 4.0, where each association explained 0.92% to 4.4% of the genetic variance and 0.01% to 1.86% of the phenotypic variance. Of these associations, only six SNP/duplication loci were located within 8 cM of a QTL peak for the trait, with two being located at the QTL peak: SST_DG156121:c.362A>G for ribeye muscle area and TG_X05380:c.422C>T for calving ease. Strong associations between several SNP/duplication loci and trait variation were obtained in the absence of any detected linked QTL. However, we reject the causality of several commercialized DNA tests, including an association between TG_X05380:c.422C>T and marbling in Angus cattle.
Monoclonal gammopathy of undetermined significance: a consensus statement
Authors: Berenson James R. , Anderson Kenneth C. , Audell Robert A. , Boccia Ralph V. , Coleman Morton , Dimopoulos Meletios A. , Drake Matthew T. , Fonseca Rafael , Harousseau Jean‐Luc , Joshua Douglas , Lonial Sagar , Niesvizky Ruben , Palumbo Antonio , Roodman G. David , San‐Miguel Jesus F. , Singhal Seema , Weber Donna M. , Zangari Maurizio , Wirtschafter Eric , Yellin Ori , Kyle Robert A. 
Published: May 2010

SummaryOn February 25, 2009, a panel of international experts on plasma cell dyscrasia and skeletal disease met to discuss monoclonal gammopathy of undetermined significance (MGUS). This non‐malignant B‐cell disorder is the most common plasma cell dyscrasia and is associated with an increased risk of developing serious B‐cell disorders. Individuals with MGUS also have an increased risk of osteoporosis and osteopenia associated with an increased likelihood of developing fractures especially in the vertebral column, peripheral neuropathy and thromboembolic events. The goal of the meeting was to develop a consensus statement regarding the appropriate tests to screen, evaluate and follow‐up patients with MGUS. The panel also addressed the identification and treatment of MGUS‐related skeletal problems, thromboembolic events and neurological complications. The following consensus statement outlines the conclusions and marks the first time that a consensus statement for the screening and treatment of MGUS has been clearly stated.
Allogeneic haematopoietic cell transplantation after nonmyeloablative conditioning in patients with T‐cell and natural killer‐cell lymphomas
Authors: Shustov Andrei R. , Gooley Theodore A. , Sandmaier Brenda M. , Shizuru Judith , Sorror Mohamed L. , Sahebi Firoozeh , McSweeney Peter , Niederwieser Dietger , Bruno Benedetto , Storb Rainer , Maloney David G. 
Published: May 2010

SummaryPatients with T‐cell and natural killer‐cell lymphomas have poor outcomes. This study examined the role of allogeneic haematopoietic cell transplantation (allo‐HCT) after nonmyeloablative conditioning in this setting. Seventeen patients with T‐cell lymphoma or NK‐cell lymphoma, including three patients in first complete remission, received allo‐HCT after 2 Gy total‐body irradiation and fludarabine. The median age was 57 (range, 18–73) years. The median number of prior therapies was 3 (range, 1–7), six patients (35%) had failed prior autologous HCT, and five patients (29%) had refractory disease at the time of allograft. Postgrafting immunosuppression was provided with mycophenolate mofetil with ciclosporin or tacrolimus. After a median follow‐up of 3·3 (range, 0·3–8·0) years among surviving patients, the estimated probabilities of 3‐year overall and progression‐free survival were 59% and 53%, respectively, while the estimated probabilities of non‐relapse mortality and relapse at 3 years were 19% and 26%, respectively. Sixty‐five percent of patients developed grades 2–4 acute graft‐versus‐host disease and 53% of patients developed chronic graft‐versus‐host disease. Allo‐HCT after nonmyeloablative conditioning is a promising salvage option for selected patients with T‐cell and NK‐cell lymphomas. These results suggest that graft‐versus‐T‐cell lymphoma activity is responsible for long‐term disease control.
Glucocerebrosidase deficiency dramatically impairs human bone marrow haematopoiesis in an in vitro model of Gaucher disease
Authors: Berger Juliette , Lecourt Séverine , Vanneaux Valérie , Rapatel Chantal , Boisgard Stéphane , Caillaud Catherine , Boiret‐Dupré Nathalie , Chomienne Christine , Marolleau Jean‐Pierre , Larghero Jérôme , Berger Marc G. 
Published: May 2010

SummaryOne of the cardinal symptoms of type 1 Gaucher Disease (GD) is cytopenia, usually explained by bone marrow (BM) infiltration by Gaucher cells and hypersplenism. However, some cases of cytopenia in splenectomized or treated patients suggest possible other mechanisms. To evaluate intra‐cellular glucocerebrosidase (GlcC) activity in immature progenitors and to prove the conduritol B epoxide (CBE)‐induced inhibition of the enzyme, we used an adapted flow cytometric technique before assessing the direct effect of GlcC deficiency in functional assays. Among haematopoietic cells from healthy donors, monocytes showed the highest GlcC activity but immature CD34+ and mesenchymal cells also had significant GlcC activity. CBE greatly inhibited the enzyme activity of all cell categories. GlcC‐deficient CD34+ cells showed impaired ability to proliferate and differentiate in the expansion assay and had lower frequency of erythroid burst‐forming units, granulocyte colony‐forming units (CFU) and macrophage CFU progenitors, but the effect of GlcC deficiency on megakaryocyte CFU lineage was not significant. GlcC deficiency strongly impaired primitive haematopoiesis in long‐term culture. Furthermore, GlcC deficiency progressively impaired proliferation of mesenchymal progenitors. These data suggest an intrinsic effect of GlcC deficiency on BM immature cells that supplements the pathophysiology of GD and opens new perspectives of therapeutic approach.
Current therapeutic approaches for patients with myelodysplastic syndromes
Authors: Greenberg Peter L. 
Published: May 2010

SummaryThe myelodysplastic syndromes (MDS) are a heterogeneous spectrum of disorders requiring selective therapy based on patients’ specific clinical features, predominantly their prognostic subgroups, age and performance status. Guidelines for management of patients with MDS have been generated by a number of national panels. This review focuses on evidence‐based data supporting therapeutic approaches, which have also been recommended by the US National Comprehensive Cancer Network MDS Panel, with discussion of accessibility of recommended drugs in the US and in other countries. For lower risk disease (International Prognostic Scoring System Low and Intermediate‐1) therapy is aimed at haematological improvement whereas for higher risk disease (Intermediate‐2 and High) treatment focuses on altering disease natural history. Recent information regarding additional clinical and biological features has provided useful parameters for assessing disease prognosis that aid risk‐based management decisions. The rationale for use of low versus high intensity therapies with these agents, including allogeneic haematopoietic stem cell transplantation, is discussed in detail.
Elevated neutrophil membrane expression of proteinase 3 is dependent upon CD177 expression
Authors: Abdgawad M , Gunnarsson L , Bengtsson A A , Geborek P , Nilsson L , Segelmark M , Hellmark T 
Published: May 2010

Summary
Proteinase 3 (PR3) is a major autoantigen in anti-neutrophil cytoplasmic antibodies (ANCA)-associated systemic vasculitis (AASV), and the proportion of neutrophils expressing PR3 on their membrane (mPR3+) is increased in AASV. We have shown recently that mPR3 and CD177 are expressed on the same cells in healthy individuals. In this study we try to elucidate mechanisms behind the increased mPR3 expression in AASV and its relationship to CD177. All neutrophils in all individuals were either double-positive or double-negative for mPR3 and CD177. The proportion of double-positive neutrophils was increased significantly in AASV and systemic lupus erythematosus patients. The proportion of mPR3+/CD177+ cells was not correlated to general inflammation, renal function, age, sex, drug treatment and levels of circulating PR3. AASV patients had normal levels of granulocyte colony-stimulating factor and granulocyte–macrophage colony-stimulating factor. Pro-PR3 was found to constitute 10% of circulating PR3 but none of the mPR3. We found increased mRNA levels of both PR3 and CD177 in AASV, but they did not correlate with the proportion of double-positive cells. In cells sorted based on membrane expression, CD177–mRNA was several-fold higher in mPR3+ cells. When exogenous PR3 was added to CD177-transfected U937 cells, only CD177+ cells bound PR3 to their membrane. In conclusion, the increased membrane expression of PR3 found in AASV is not linked directly to circulating PR3 or PR3 gene transcription, but is dependent upon CD177 expression and correlated with the transcription of the CD177 gene.
The immunotherapeutic potential of dendritic cells in type 1 diabetes
Authors: Mukherjee G , DiLorenzo T P 
Published: May 2010

SummaryType 1 diabetes is an autoimmune disease characterized by destruction of the pancreatic islet beta cells that is mediated primarily by T cells specific for beta cell antigens. Insulin administration prolongs the life of affected individuals, but often fails to prevent the serious complications that decrease quality of life and result in significant morbidity and mortality. Thus, new strategies for the prevention and treatment of this disease are warranted. Given the important role of dendritic cells (DCs) in the establishment of peripheral T cell tolerance, DC-based strategies are a rational and exciting avenue of exploration. DCs employ a diverse arsenal to maintain tolerance, including the induction of T cell deletion or anergy and the generation and expansion of regulatory T cell populations. Here we review DC-based immunotherapeutic approaches to type 1 diabetes, most of which have been employed in non-obese diabetic (NOD) mice or other murine models of the disease. These strategies include administration of in vitro-generated DCs, deliberate exposure of DCs to antigens before transfer and the targeting of antigens to DCs in vivo. Although remarkable results have often been obtained in these model systems, the challenge now is to translate DC-based immunotherapeutic strategies to humans, while at the same time minimizing the potential for global immunosuppression or exacerbation of autoimmune responses. In this review, we have devoted considerable attention to antigen-specific DC-based approaches, as results from murine models suggest that they have the potential to result in regulatory T cell populations capable of both preventing and reversing type 1 diabetes.
TP53 mutations coincide with the ectopic expression of activation-induced cytidine deaminase in the fibroblast-like synoviocytes derived from a fraction of patients with rheumatoid arthritis
Authors: Igarashi H , Hashimoto J , Tomita T , Yoshikawa H , Ishihara K 
Published: May 2010

Summary
Main features of rheumatoid arthritis (RA), hyperplasia of fibroblast-like synoviocytes (FLS) and joint destruction are caused by inflammatory cytokines produced in chronic autoimmune inflammation. Cell-intrinsic acquisition of tumour-like phenotypes of RA-FLS could also be responsible for the aggressive proliferation and invasion, which are supported by the fact that in some cases RA-FLS has mutations of a tumour suppressor gene TP53. However, the underlying molecular mechanism for TP53 mutations in RA-FLS has not yet been clarified. Recently it has been reported that the non-lymphoid cells in the inflammatory tissues express ectopically the activation-induced cytidine deaminase (AID) gene that induces somatic hypermutations, not only at the immunoglobulin (Ig) gene variable regions in germinal centre B lymphocytes but also at coding regions in TP53. Real-time polymerase chain reaction (PCR) analyses revealed more than half (five of nine) of the RA-FLS lines we established showed the markedly increased expression of AID. AID transcription in RA-FLS was augmented by tumour necrosis factor (TNF)-α and even by physiological concentration of β-oestradiol that could not induce AID transcription in osteoarthritis-FLS. Furthermore, AID-positive RA-FLS presented a higher frequency of somatic mutations in TP53. Cytological and immunohistochemical analyses demonstrated clearly the ectopic expression of AID in the FLS at the RA synovium. These data suggested strongly a novel consequence of RA; the ectopic expression of AID in RA-FLS causes the somatic mutations and dysfunction of TP53, leading to acquisition of tumour-like properties by RA-FLS.
Presence of intestinal helminths decreases T helper type 1 responses in tuberculoid leprosy patients and may increase the risk for multi-bacillary leprosy
Authors: Diniz L M , Magalhães E F L , Pereira F E L , Dietze R , Ribeiro-Rodrigues R 
Published: May 2010

SummaryResistance to intracellular pathogens such as Mycobacterium leprae is dependent upon an effective T helper type 1 (Th1)-type immune response. On the other hand, intestinal helminths are known to subvert the host's immune response towards to either a Th2-type immune response or a regulatory T cell up-regulation, which may affect the host's ability to mount an effective response to mycobacteria. Here, we report a significant association between intestinal helminth infections and lepromatous leprosy [odds ratio (OR), 10·88; confidence interval (CI) 95%: 4·02–29·4; P &lt; 0·001]. We also observed that the frequency of intestinal helminths correlated strongly with the mycobacterial index (r = 0·982, P &lt; 0·01). Corroborating with our hypothesis, intracellular levels of interferon-γ were decreased significantly in leprosy patients co-infected with intestinal helminths when compared to leprosy patients without worms. Conversely, lepromatous leprosy patients with intestinal worms produced higher levels of both interleukin (IL)-4 and IL-10. Our results suggest that a pre-existing infection by intestinal helminths may facilitate the establishment of M. leprae infection or its progression to more severe forms of leprosy.
A crucial role of sialidase Neu1 in hyaluronan receptor function of CD44 in T helper type 2-mediated airway inflammation of murine acute asthmatic model
Authors: Katoh S , Maeda S , Fukuoka H , Wada T , Moriya S , Mori A , Yamaguchi K , Senda S , Miyagi T 
Published: May 2010

SummaryCD44 is a highly glycosylated cell adhesion molecule that is involved in lymphocyte infiltration of inflamed tissues. We have demonstrated previously that sialic acid residues of CD44 negatively regulates its receptor function and CD44 plays an important role in the accumulation of T helper type 2 (Th2) cells in the airway of a murine model of acute asthma. Here we evaluated the role of sialidase in the hyaluronic acid (HA) receptor function of CD44 expressed on CD4+ T cells, as well as in the development of a mite antigen-induced murine model of acute asthma. Splenic CD4+ T cell binding of HA was examined with flow cytometry. Expression of sialidases (Neu1, Neu2, Neu3 and Neu4) in spleen cells was evaluated by quantitative real-time reverse transcription–polymerase chain reaction. Airway inflammation and airway hyperresponsiveness (AHR) were evaluated in the asthmatic Neu1-deficient mouse strain SM/J model. Splenic CD4+ T cells from asthmatic model mice displayed increased HA receptor activity of CD44 after culture with the antigen, along with characteristic parallel induction of sialidase (Neu1) expression. This induction of HA binding was suppressed significantly by a sialidase inhibitor and was not observed in SM/J mice. Th2 cytokine concentration and absolute number of Th2 cells in the bronchoalveolar lavage fluid, and AHR were decreased in SM/J mice. In conclusion, HA receptor activity of CD44 and acute asthmatic reactions, including Th2-mediated airway inflammation and AHR, are dependent upon Neu1 enzymatic activity. Our observation suggests that Neu1 may be a target molecule for the treatment of asthma.
In vivo manipulation of Vγ9Vδ2 T cells with zoledronate and low-dose interleukin-2 for immunotherapy of advanced breast cancer patients
Authors: Meraviglia S , Eberl M , Vermijlen D , Todaro M , Buccheri S , Cicero G , La Mendola C , Guggino G , D'Asaro M , Orlando V , Scarpa F , Roberts A , Caccamo N , Stassi G , Dieli F , Hayday A C 
Published: May 2010

Summary
The potent anti-tumour activities of γδ T cells have prompted the development of protocols in which γδ-agonists are administered to cancer patients. Encouraging results from small Phase I trials have fuelled efforts to characterize more clearly the application of this approach to unmet clinical needs such as metastatic carcinoma. To examine this approach in breast cancer, a Phase I trial was conducted in which zoledronate, a Vγ9Vδ2 T cell agonist, plus low-dose interleukin (IL)-2 were administered to 10 therapeutically terminal, advanced metastatic breast cancer patients. Treatment was well tolerated and promoted the effector maturation of Vγ9Vδ2 T cells in all patients. However, a statistically significant correlation of clinical outcome with peripheral Vγ9Vδ2 T cell numbers emerged, as seven patients who failed to sustain Vγ9Vδ2 T cells showed progressive clinical deterioration, while three patients who sustained robust peripheral Vγ9Vδ2 cell populations showed declining CA15-3 levels and displayed one instance of partial remission and two of stable disease, respectively. In the context of an earlier trial in prostate cancer, these data emphasize the strong linkage of Vγ9Vδ2 T cell status to reduced carcinoma progression, and suggest that zoledronate plus low-dose IL-2 offers a novel, safe and feasible approach to enhance this in a subset of treatment-refractory patients with advanced breast cancer.