Budesonide and Formoterol Reduce Early Innate Anti-Viral Immune Responses In Vitro

Asthma is a chronic inflammatory airways disease in which respiratory viral infections frequently trigger exacerbations. Current treatment of asthma with combinations of inhaled corticosteroids and long acting beta2 agonists improves asthma control and reduces exacerbations but what impact this might have on innate anti-viral immunity is unclear. We investigated the in vitro effects of asthma drugs on innate anti-viral immunity. Peripheral blood mononuclear cells (PBMC) from healthy and asthmatic donors were cultured for 24 hours with the Toll-like receptor 7 agonist, imiquimod, or rhinovirus 16 (RV16) in the presence of budesonide and/or formoterol. Production of proinflammatory cytokines and expression of anti-viral intracellular signalling molecules were measured by ELISA and RT-PCR respectively. In PBMC from healthy donors, budesonide alone inhibited IP-10 and IL-6 production induced by imiquimod in a concentration-dependent manner and the degree of inhibition was amplified when budesonide and formoterol were used in combination. Formoterol alone had little effect on these parameters, except at high concentrations (10−6 M) when IL-6 production increased. In RV16 stimulated PBMC, the combination of budesonide and formoterol inhibited IFNα and IP-10 production in asthmatic as well as healthy donors. Combination of budesonide and formoterol also inhibited RV16-stimulated expression of the type I IFN induced genes myxovirus protein A and 2′, 5′ oligoadenylate synthetise. Notably, RV16 stimulated lower levels of type Myxovirus A and oligoadenylate synthase in PBMC of asthmatics than control donors. These in vitro studies demonstrate that combinations of drugs commonly used in asthma therapy inhibit both early pro-inflammatory cytokines and key aspects of the type I IFN pathway. These findings suggest that budesonide and formoterol curtail excessive inflammation induced by rhinovirus infections in patients with asthma, but whether this inhibits viral clearance in vivo remains to be determined

Limited genetic variation and structure in softshell clams (Mya arenaria) across their native and introduced range

Author Posting. © Springer, 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Conservation Genetics 10 (2009): 803-814, doi:10.1007/s10592-008-9641-y.To offset declines in commercial landings of the softshell clam, Mya arenaria, resource managers are engaged in extensive stocking of seed clams throughout its range in the northwest Atlantic. Because a mixture of native and introduced stocks can disrupt locally adapted genotypes, we investigated genetic structure in M. arenaria populations across its current distribution to test for patterns of regional differentiation. We sequenced mitochondrial cytochrome oxidase I (COI) for a total of 212 individuals from 12 sites in the northwest Atlantic (NW Atlantic), as well as two introduced sites, the northeast Pacific (NE Pacific) and the North Sea and Europe (NS Europe). Populations exhibited extremely low genetic variation, with one haplotype dominating (65-100%) at all sites sampled. Despite being introduced in the last 150-400 years, both NE Pacific and NS Europe populations had higher diversity measures than those in the NW Atlantic and both contained private haplotypes at frequencies of 10% to 27% consistent with their geographic isolation. While significant genetic structure (FST = 0.159, p<0.001) was observed between NW Atlantic and NS Europe, there was no evidence for genetic structure across the pronounced environmental clines of the NW Atlantic. Reduced genetic diversity in mtDNA combined with previous studies reporting reduced genetic diversity in nuclear markers strongly suggests a recent population expansion in the NW Atlantic, a pattern that may result from the retreat of ice sheets during Pleistocene glacial periods. Lack of genetic diversity and regional genetic differentiation suggests that present management strategies for the commercially important softshell clam are unlikely to have a significant impact on the regional distribution of genetic variation, although the possibility of disrupting locally adapted stocks cannot be excluded.This work was supported by NSF grants OCE-0326734 and OCE-0215905 to L. Mullineaux and OCE- 0349177 (Biological Oceanography) to PHB

Searching for converging research using field to field citations

We define converging research as the emergence of an interdisciplinary research area from fields that did not show interdisciplinary connections before. This paper presents a process to search for converging research using journal subject categories as a proxy for fields and citations to measure interdisciplinary connections, as well as an application of this search. The search consists of two phases: a quantitative phase in which pairs of citing and cited fields are located that show a significant change in number of citations, followed by a qualitative phase in which thematic focus is sought in publications associated with located pairs. Applying this search on publications from the Web of Science published between 1995 and 2005, 38 candidate converging pairs were located, 27 of which showed thematic focus, and 20 also showed a similar focus in the other, reciprocal pair

Altered maturation of peripheral blood dendritic cells in patients with breast cancer

Tumours have at least two mechanisms that can alter dendritic cell (DC) maturation and function. The first affects the ability of haematopoietic progenitors to differentiate into functional DCs; the second affects their differentiation from CD14+ monocytes, promoting an early but dysfunctional maturation. The aim of this study was to evaluate the in vivo relevance of these pathways in breast cancer patients. For this purpose, 53 patients with invasive breast cancer were compared to 68 healthy controls. To avoid isolation or culture procedures for enrichment of DCs, analyses were directly performed by flow cytometry on whole-blood samples. The expression of surface antigens and intracellular accumulation of regulatory cytokines upon LPS stimulation were evaluated. The number of DCs, and in particular of the myeloid subpopulation, was markedly reduced in cancer patients (P < 0.001). Patient DCs were characterized by a more mature phenotype compared with controls (P = 0.016), and had impaired production of IL-12 (P < 0.001), These alterations were reverted by surgical resection of the tumour. To investigate the possible role of some tumour-related immunoactive soluble factors, we measured the plasmatic levels of vascular endothelial growth factor, IL-10 and spermine. A significant inverse correlation between spermine concentration and the percentage of DCs expressing IL-12 was found. Evidence was also obtained that in vitro exposure of monocyte-derived DCs to spermine promoted their activation and maturation, and impaired their function. Taken together, our results suggest that both the above-described mechanisms could concomitantly act in breast cancer to affect DC differentiation, and that spermine could be a mediator of dysfunctional maturation of DCs

Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells

Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an ‘immature’ neonatal to a ‘mature’ adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation

The situational logic of disciplinary scholarship

Ian C. Jarvie developed the idea of situational logic in a subtle and effective way. He was also interested in, as well as a contributor to, the institution of academic publication. This chapter provides a situational analysis of an important recurrent pattern in academic publishing, namely, the concentration of work around particular topics, despite the fact that most such work will be unrewarded in the economy of esteem that is meant to be in play