bluuebunny/crossref_metadata_2025_split huggingface dataset:
Therapeutic granulocyte and monocyte apheresis (GMA) for treatment refractory sarcoidosis: a pilot study of clinical effects and possible mechanisms of action
Authors: Olsen H H , Muratov V , Cederlund K , Lundahl J , Eklund A , Grunewald J 
Published: April 2014

SummarySarcoidosis is a systemic, inflammatory disorder, which in a proportion of patients runs a chronic progressive course despite immunosuppressive treatment. Therapeutic granulocyte and monocyte apheresis (GMA) has been shown to be an effective treatment option for other systemic inflammatory disorders, but has not yet been investigated in sarcoidosis. The aim of this study was to evaluate the response to GMA in sarcoidosis. Seven patients with sarcoidosis refractory to standard immunosuppressive therapy received 10 GMA sessions. All patients underwent chest X-ray, spirometry, a Chronic Respiratory Disease Questionnaire (CRQ-SAS), blood tests and bronchoscopy with bronchoalveolar lavage (BAL) before treatment and at 2–4 weeks and 3 months (except bronchoscopy) after the last treatment session. Bronchoalveolar lavage fluid (BALF) cell differential counts were recorded and T cells from blood and BALF were analysed for markers of activity, differentiation and T regulatory function. Compared to baseline, five of seven patients reported an improvement in dyspnoea score. In BALF there was an increase in the percentage of macrophages and a decrease in the percentage of lymphocytes and CD4+/FoxP3+T cells. Furthermore, the decrease in BALF CD4+/FoxP3+T cells correlated significantly with an improvement in dyspnoea score. In peripheral blood there was a statistically significant increase in the percentage of CD4+/CD27−T cells and a trend towards an initial increase in the percentage of CD4+/FoxP3+T cells, followed by a statistically significant decrease. The effects of GMA on regulatory T cells are consistent with those observed in other inflammatory disorders and could potentially translate into a clinical benefit.
Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes
Authors: Thompson W S , Pekalski M L , Simons H Z , Smyth D J , Castro-Dopico X , Guo H , Guy C , Dunger D B , Arif S , Peakman M , Wallace C , Wicker L S , Todd J A , Ferreira R C 
Published: April 2014

SummaryThe appearance of circulating islet-specific autoantibodies before disease diagnosis is a hallmark of human type 1 diabetes (T1D), and suggests a role for B cells in the pathogenesis of the disease. Alterations in the peripheral B cell compartment have been reported in T1D patients; however, to date, such studies have produced conflicting results and have been limited by sample size. In this study, we have performed a detailed characterization of the B cell compartment in T1D patients (n = 45) and healthy controls (n = 46), and assessed the secretion of the anti-inflammatory cytokine interleukin (IL)-10 in purified B cells from the same donors. Overall, we found no evidence for a profound alteration of the B cell compartment or in the production of IL-10 in peripheral blood of T1D patients. We also investigated age-related changes in peripheral B cell subsets and confirmed the sharp decrease with age of transitional CD19+CD27−CD24hiCD38hiB cells, a subset that has recently been ascribed a putative regulatory function. Genetic analysis of the B cell compartment revealed evidence for association of the IL2–IL21 T1D locus with IL-10 production by both memory B cells (P = 6·4 × 10−4) and islet-specific CD4+T cells (P = 2·9 × 10−3). In contrast to previous reports, we found no evidence for an alteration of the B cell compartment in healthy individuals homozygous for the non-synonymous PTPN22 Trp620T1D risk allele (rs2476601; Arg620Trp). The IL2–IL21 association we have identified, if confirmed, suggests a novel role for B cells in T1D pathogenesis through the production of IL-10, and reinforces the importance of IL-10 production by autoreactive CD4+T cells.
The expression of Toll-like receptors 2, 4 and 9 in kidneys of patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis
Authors: Wang H , Gou S-J , Zhao M-H , Chen M 
Published: April 2014

Summary
Increasing evidence suggested that Toll-like receptors (TLRs) were critically involved in immune responses of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to investigate the expression of TLR-2, TLR-4 and TLR-9 in kidneys of patients with ANCA-associated vasculitis. Renal biopsy specimens were collected from 24 patients with AAV. The expression of TLR-2, TLR-4 and TLR-9 in kidneys was detected by immunohistochemistry. Double immunofluorescence staining was performed to detect the expression of TLRs on various kinds of cells. In renal specimens, immunohistochemical examination revealed that expression of TLR-2 and TLR-4 could be detected in the glomeruli of AAV patients, while TLR-2 and TLR-4 were scarcely detected in the glomeruli of normal controls. Double immunofluorescence staining of TLR-2, TLR-4 and CD31 indicated that TLR-4 and TLR-2 were expressed on endothelial cells in the glomeruli. In the tubulointerstitial compartment, expression of TLR-2, TLR-4 and TLR-9 could be detected in both AAV patients and normal controls. The mean optical density of TLR-2 and TLR-4 in the tubulointerstitial compartment in AAV patients were significantly higher than that in normal controls. Among AAV patients, correlation analysis showed that the mean optical density of TLR-4 in the glomeruli correlated inversely with the initial serum creatinine, the proportion of total crescents and the proportion of cellular crescents in renal specimens (r = −0·419, P = 0·041; r = −0·506, P = 0·012; r = −0·505, P = 0·012, respectively). The expression of TLR-2 and TLR-4 was dysregulated in kidneys of AAV patients. The expression of TLR-4 in glomeruli was associated with the severity of renal injury.
Intestinal titres of anti-tissue transglutaminase 2 antibodies correlate positively with mucosal damage degree and inversely with gluten-free diet duration in coeliac disease
Authors: Tosco A , Auricchio R , Aitoro R , Ponticelli D , Primario M , Miele E , Rotondi Aufiero V , Discepolo V , Greco L , Troncone R , Maglio M 
Published: April 2014

Summary
It has always been known that anti-tissue transglutaminase 2 (anti-TG2) antibodies are produced in the small intestine. Their serum titres correlate with mucosal damage degree and decrease on a gluten-free diet (GFD).
We aimed to correlate intestinal anti-TG2 antibodies levels with degree of mucosal damage and GFD duration.
Thirty-four active, 71 potential and 24 CD patients on GFD for at least 2 years were enrolled. Anti-TG2 deposits were detected in intestinal biopsies by double immunofluorescence. Biopsies were cultured for 24 h with medium, and with gliadin peptic tryptic digest (PTG) or A-gliadin peptide 31–43 (P31-43). Anti-TG2 antibodies secreted into supernatants were measured by enzyme-linked immunosorbent assay (ELISA). All active CD patients secreted high titres of anti-TG2 antibodies into culture medium that increased with the worsening of mucosal injury (Spearman's r = 0·71; P &lt; 0·0001). Seventy of 71 potential CD patients and 15 of 24 treated CD patients secreted low titres of anti-TG2 antibodies into supernatants, eight of nine negative treated patients being on GFD for more than 10 years. An inverse correlation between antibody titres and duration of GFD was found, (Spearman's r = −0·52; P &lt; 0·01). All active, 53 of 71 potential and six of 24 treated, CD patients showed anti-TG2 mucosal deposits. Five of six positive treated CD patients had been on GFD for fewer than 6 years and were also positive for secreted anti-TG2. In treated patients, PTG/P31-43 was not able to induce secretion of anti-TG2 antibodies into culture medium.
Measurement of anti-TG2 antibodies in biopsy supernatants proved to be more sensitive than detection by immunofluorescence to reveal their intestinal production. Intestinal antiTG2 antibodies titres correlated positively with the degree of mucosal damage and inversely with the duration of GFD.
Abatacept (cytotoxic T lymphocyte antigen 4-immunoglobulin) improves B cell function and regulatory T cell inhibitory capacity in rheumatoid arthritis patients non-responding to anti-tumour necrosis factor-α agents
Authors: Picchianti Diamanti A , Rosado M M , Scarsella M , Germano V , Giorda E , Cascioli S , Laganà B , D'Amelio R , Carsetti R 
Published: April 2014

Summary
The use of biological agents combined with methotrexate (MTX) in rheumatoid arthritis (RA) patients has strongly improved disease outcome. In this study, the effects of abatacept on the size and function of circulating B and T cells in RA patients not responding to anti-tumour necrosis factor (TNF)-α have been analysed, with the aim of identifying immunological parameters helpful to choosing suitable tailored therapies. We analysed the frequency of peripheral B and T cell subsets, B cell function and T regulatory cell (Treg) inhibitory function in 20 moderate/severe RA patients, according to the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria, primary non-responders to one TNF-α blocking agent, who received abatacept + MTX. Patients were studied before and 6 months after therapy. We found that abatacept therapy significantly reduced disease activity score on 44 joints (DAS)/erythrocyte sedimentation rate (ESR) values without causing severe side effects. The size of the circulating B and T cell compartments in RA patients was not significantly different from healthy donors, but B cell proliferation and plasma cell differentiation was impaired before therapy and restored by abatacept. While Treg cell frequency was normal, its inhibitory function was absent before therapy and was partially recovered 6 months after abatacept. B and Treg cell function is impaired in RA patients not responding to the first anti-TNF-α agent. Abatacept therapy was able to rescue immune function and led to an effective and safe clinical outcome, suggesting that RA patients, in whom anti-TNF-α failed, are immunologically prone to benefit from an agent targeting a different pathway.
Type III interferons are expressed by Coxsackievirus-infected human primary hepatocytes and regulate hepatocyte permissiveness to infection
Authors: Lind K , Svedin E , Utorova R , Stone V M , Flodström-Tullberg M 
Published: April 2014

Summary
Hepatitis is a common and potentially fatal manifestation of severe Coxsackievirus infections, particularly in newborn children. Little is known of the immune-mediated mechanisms regulating permissiveness to liver infection. It is well established that type I interferons (IFNs) play an important role in the host innate immune response to Coxsackievirus infections. Recent studies have highlighted a role for another IFN family, the type III IFNs (also called IFN-λ), in anti-viral defence. Whether type III IFNs are produced by hepatocytes during a Coxsackievirus infection remains unknown. Moreover, whether or not type III IFNs protects hepatocytes from a Coxsackievirus infection has not been addressed. In this study, we show that primary human hepatocytes respond to a Coxsackievirus B3 (CVB3) infection by up-regulating the expression of type III IFNs. We also demonstrate that type III IFNs induce an anti-viral state in hepatocytes characterized by the up-regulated expression of IFN-stimulated genes, including IFN-stimulated gene (ISG15), 2′-5′-oligoadenylate synthetase 2 (OAS2), protein kinase regulated by dsRNA (PKR) and myxovirus resistance protein 1 (Mx1). Furthermore, our study reveals that type III IFNs attenuate CVB3 replication both in hepatocyte cell lines and primary human hepatocytes. Our studies suggest that human hepatocytes express type III IFNs in response to a Coxsackievirus infection and highlight a novel role for type III IFNs in regulating hepatocyte permissiveness to this clinically relevant type of virus.
Noradrenergic Terminals Regulate l‐DOPA‐derived Dopamine Extracellular Levels in a Region‐dependent Manner in Parkinsonian Rats
Authors: Navailles Sylvia , Milan Léa , Khalki Hanane , Di Giovanni Giuseppe , Lagière Mélanie , De Deurwaerdère Philippe 
Published: April 2014

SummaryAimsSerotonin (5‐HT) neurons mediate the ectopic release of dopamine (DA) induced by l‐DOPA in the Parkinsonian brain. We hypothesized that the participation of noradrenalin transporters (NET) in the clearance of DA may account for the lower effect of l‐DOPA in extrastriatal regions compared with the striatum.MethodsUsing a multisite intracerebral microdialysis approach, we tested the influence of the pharmacological blockade of NET and/or the destruction of noradrenalin (NE) fibers on DA and 5‐HT release in the striatum, hippocampus (HIPP), substantia nigra pars reticulata (SNr) and prefrontal cortex (PFC) of 6‐hydroxydopamine‐lesioned rats.Resultsl‐DOPA (12 mg/kg, i.p.) increased DA extracellular levels to a lesser extent in the SNr, PFC and HIPP compared with the striatum. The NET blockers desipramine (10 mg/kg, i.p.) and reboxetine (3 mg/kg, i.p.) potentiated l‐DOPA effect in the PFC, SNr and HIPP but not in the striatum. The NE neurotoxin N‐(2‐chloroethyl)‐N‐ethyl‐2‐bromobenzylamine (50 mg/kg, i.p. 1 week before dialysis experiment) potentiated l‐DOPA effect in the SNr and HIPP. 5‐HT extracellular levels were enhanced only when l‐DOPA was combined to NET blockers.ConclusionNoradrenalin neurons are indirectly involved in the mechanism of action of l‐DOPA in part through the heterologous reuptake of DA in extrastriatal regions.
Conserving Biodiversity Through Certification of Tropical Agroforestry Crops at Local and Landscape Scales
Authors: Tscharntke Teja , Milder Jeffrey C. , Schroth Götz , Clough Yann , DeClerck Fabrice , Waldron Anthony , Rice Robert , Ghazoul Jaboury 
Published: April 2014

AbstractVoluntary sustainability standards and certification offer a promising mechanism to mitigate the severe negative impacts of agricultural expansion and intensification on tropical biodiversity. From a conservation standpoint, certification of tropical agroforestry crops, especially coffee and cocoa, is of particular interest given the potentially high biodiversity value of agroforestry systems and the substantial market penetration of coffee and cocoa certification in recent years. Here, we review experience with coffee and cocoa certification, summarize evidence on conservation impacts, and explore future needs. While there is much evidence that environmental criteria behind certification support biodiversity conservation, it is less clear to what extent certification is the cause of improved conservation outcomes. Additionally, the farm‐scale focus of current certification models may limit delivery of biodiversity conservation benefits, as maintenance of biodiversity depends on processes at larger landscape scales. To address this scale mismatch, we suggest that investment and innovation in certification over the next decade prioritize landscape conservation outcomes. This may be achieved by (1) linking existing certification mechanisms with broader landscape and ecosystem service management approaches and/or (2) expanding current certification models to consider the landscape itself as the certified unit.
Challenging the Scientific Foundations for an IUCN Red List of Ecosystems
Authors: Boitani Luigi , Mace Georgina M. , Rondinini Carlo 
Published: April 2014

AbstractThe International Union for Conservation of Nature (IUCN) is currently discussing the development of a Red List of Ecosystems (RLE) that would mirror the categories and criteria used to assess the conservation status of species. The suggested scientific foundations for the RLE are being considered by IUCN for adoption as the backbone of the RLE. We identify conceptual and operational weaknesses in the draft RLE approach, the categories, and criteria. While species are relatively well‐described units, there is no consistent means to classify ecosystems for assessing conservation status. The proposed RLE is framed mostly around certain features of ecosystems such as broad vegetation or habitat types, and do not consider major global change drivers such as climate change. We discuss technical difficulties with the proposed concept of ecosystem collapse and suggest it is not analogous to species extinction. We highlight the lack of scientific basis for the criteria and thresholds proposed by the RLE, and question the need to adopt the structure of the Red List of Species for an RLE. We suggest that the proposed RLE is open to ambiguous interpretations and uncertain outcomes, and that its practicality and benefit for conservation should be carefully evaluated before final approval.
Governance Strategies for Conducting Text Messaging Interventions in Clinical Research
Authors: Anderson Nicholas , Morrison Caitlin , Griffin Jonathan , Reiter William , Baldwin Laura‐Mae , Edwards Kelly 
Published: April 2014

AbstractThere is increasing interest in medical text messaging interventions being used to achieve positive patient outcomes across a range of clinical research and health practice environments. Short messaging service (SMS) is a low‐cost tool that provides an easy communication route to engage potentially broad populations through text messaging, and is part of the growing social trend toward increased adoption of personal communication technologies by patient populations. Testing the effectiveness and impact of various communication strategies requires navigation of a complex web of clinical and research regulations and oversight mechanisms. We describe a case study of the implementation of SMS to provide bidirectional communications between physicians and patients involved in routine care reminders to illustrate the review processes and governance structures needed. By mapping the regulatory and approval processes required to manage and steward a research study across clinical and community boundaries, we provide a guide for other translational health researchers who may utilize similar kinds of personally owned technology interventions as research tools.
Cancer stem cells and their implication in breast cancer
Authors: Carrasco E. , Álvarez Pablo J. , Prados José , Melguizo Consolación , Rama Ana R. , Aránega Antonia , Rodríguez‐Serrano Fernando 
Published: April 2014

AbstractBackgroundThe cancer stem cell (CSC) hypothesis on the origin of cancer has recently gained considerable support. CSCs are tumour cells with the capacity for self‐renewal and differentiation that direct the origin and progression of the disease and may be responsible for relapse, metastasis and treatment failures.DesignThis article reviews breast CSCs (BCSCs) phenotyping, clinical implications and clinical trials focused on BCSCs in breast cancer. Relevant studies were found through PubMed and Clinicaltrials.gov databases.ResultsCancer stem cells are identified and isolated using membrane and cell activity markers; in the case of BCSCs, these are CD44+/CD24low/− and show aldehyde dehydrogenase activity, alongside their capacity to grow and form mammospheres. The presence of stem cell properties is associated with a worse outcome. Hence, these cells have important clinical implications, and elucidation of the mechanisms underlying their activity will allow the development of novel effective therapies and diagnostic instruments, improving the prognosis of these patients.ConclusionsStandard treatments are directed against the tumour mass and do not eliminate CSCs. There is therefore a need for specific anti‐CSC therapies, and numerous authors are investigating new targets to this end, as reported in this review. It is also necessary for clinical trials to be undertaken to allow this new knowledge to be applied in the clinical setting. However, there have been few trials on anti‐BCSCs therapies to date.
Correlated evolution in parental care in females but not males in response to selection on paternity assurance behaviour
Authors: Head Megan L. , Hinde Camilla A. , Moore Allen J. , Royle Nick J. 
Published: April 2014

AbstractAccording to classical parental care theory males are expected to provide less parental care when offspring in a brood are less likely to be their own, but empirical evidence in support of this relationship is equivocal. Recent work predicts that social interactions between the sexes can modify co‐evolution between traits involved in mating and parental care as a result of costs associated with these social interactions (i.e. sexual conflict). In burying beetles (Nicrophorus vespilloides), we use artificial selection on a paternity assurance trait, and crosses within and between selection lines, to show that selection acting on females, not males, can drive the co‐evolution of paternity assurance traits and parental care. Males do not care more in response to selection on mating rate. Instead, patterns of parental care change as an indirect response to costs of mating for females.
Phylogenetic relatedness and the determinants of competitive outcomes
Authors: Godoy Oscar , Kraft Nathan J. B. , Levine Jonathan M. 
Published: April 2014

AbstractRecent hypotheses argue that phylogenetic relatedness should predict both the niche differences that stabilise coexistence and the average fitness differences that drive competitive dominance. These still largely untested predictions complicate Darwin's hypothesis that more closely related species less easily coexist, and challenge the use of community phylogenetic patterns to infer competition. We field parameterised models of competitor dynamics with pairs of 18 California annual plant species, and then related species' niche and fitness differences to their phylogenetic distance. Stabilising niche differences were unrelated to phylogenetic distance, while species' average fitness showed phylogenetic structure. This meant that more distant relatives had greater competitive asymmetry, which should favour the coexistence of close relatives. Nonetheless, coexistence proved unrelated to phylogeny, due in part to increasing variance in fitness differences with phylogenetic distance, a previously overlooked property of such relationships. Together, these findings question the expectation that distant relatives should more readily coexist.