Genome-level longitudinal expression of signaling pathways and gene networks in pediatric septic shock

We have conducted longitudinal studies focused on the expression profiles of signaling pathways and gene networks in children with septic shock. Genome-level expression profiles were generated from whole blood-derived RNA of children with septic shock (n=30) corresponding to day one and day three of septic shock, respectively. Based on sequential statistical and expression filters, day one and day three of septic shock were characterized by differential regulation of 2,142 and 2,504 gene probes, respectively, relative to controls (n=15). Venn analysis demonstrated 239 unique genes in the day one dataset, 598 unique genes in the day three dataset, and 1,906 genes common to both datasets. Functional analyses demonstrated time-dependent, differential regulation of genes involved in multiple signaling pathways and gene networks primarily related to immunity and inflammation. Notably, multiple and distinct gene networks involving T cell- and MHC antigen-related biology were persistently downregulated on both day one and day three. Further analyses demonstrated large scale, persistent downregulation of genes corresponding to functional annotations related to zinc homeostasis. These data represent the largest reported cohort of patients with septic shock subjected to longitudinal genome-level expression profiling. The data further advance our genome-level understanding of pediatric septic shock and support novel hypotheses.     

New concepts of IL-10-induced lung fibrosis: fibrocyte recruitment and M2 activation in a CCL2/CCR2 axis

IL-10 is most commonly recognized as an anti-inflammatory cytokine possessing immunosuppressive effects necessary for regulated resolution of proinflammation. However, its role in the development of fibrosis during inflammatory resolution has not been clear. Few prior studies have linked IL-10 with the inhibition of fibrosis principally on the basis of regulating inflammation thought to be driving fibroproliferation. In contrast, in a model of long-term overexpression of IL-10, we observed marked induction of lung fibrosis in mice. The total cell number retrieved by bronchoalveolar lavage (BAL) increased 10-fold in the IL-10 overexpression (IL-10 OE) mice, with significant infiltration of T and B lymphocytes and collagen-producing cells. The presence of increased fibrocytes, isolated from collagenase-digested lungs, was identified by flow cytometry using dual staining of CD45 and collagen 1. Quantitative PCR analysis on an array of chemokine/chemokine receptor genes showed that receptor CCR2 and its ligand, CCL2, were highly upregulated in IL-10 OE mice, suggesting that IL-10-induced fibrocyte recruitment was CCL2/CCR2 specific. Given the prior association of alternatively activated (M(2)) macrophages with development of fibrosis in other disease states, we also examined the effect of IL-10 OE on the M(2) macrophage axis. We observed significantly increased numbers of M(2) macrophages in both BAL and whole lung tissue from the IL-10 OE mice. Administration of rabbit anti-CCL2 antiserum to IL-10 OE mice for three consecutive weeks significantly decreased fibrosis as evidenced by lung hydroxyproline content, compared with mice that received preimmune rabbit serum. These results indicate that overexpression of IL-10 induces fibrosis, in part, by fibrocyte recruitment and M(2) macrophage activation, and likely in a CCL2/CCR2 axis.     

Attitudinal and demographic predictors of measles-mumps-rubella vaccine (MMR) uptake during the UK catch-up campaign 2008-09: cross-sectional survey

Background and Objective

Continued suboptimal measles-mumps-rubella (MMR) vaccine uptake has re-established measles epidemic risk, prompting a UK catch-up campaign in 2008–09 for children who missed MMR doses at scheduled age. Predictors of vaccine uptake during catch-ups are poorly understood, however evidence from routine schedule uptake suggests demographics and attitudes may be central. This work explored this hypothesis using a robust evidence-based measure.

Design

Cross-sectional self-administered questionnaire with objective behavioural outcome.

Setting and Participants

365 UK parents, whose children were aged 5–18 years and had received <2 MMR doses before the 2008–09 UK catch-up started.

Main Outcome Measures

Parents'' attitudes and demographics, parent-reported receipt of invitation to receive catch-up MMR dose(s), and catch-up MMR uptake according to child''s medical record (receipt of MMR doses during year 1 of the catch-up).

Results

Perceived social desirability/benefit of MMR uptake (OR = 1.76, 95% CI = 1.09–2.87) and younger child age (OR = 0.78, 95% CI = 0.68–0.89) were the only independent predictors of catch-up MMR uptake in the sample overall. Uptake predictors differed by whether the child had received 0 MMR doses or 1 MMR dose before the catch-up. Receipt of catch-up invitation predicted uptake only in the 0 dose group (OR = 3.45, 95% CI = 1.18–10.05), whilst perceived social desirability/benefit of MMR uptake predicted uptake only in the 1 dose group (OR = 9.61, 95% CI = 2.57–35.97). Attitudes and demographics explained only 28% of MMR uptake in the 0 dose group compared with 61% in the 1 dose group.

Conclusions

Catch-up MMR invitations may effectively move children from 0 to 1 MMR doses (unimmunised to partially immunised), whilst attitudinal interventions highlighting social benefits of MMR may effectively move children from 1 to 2 MMR doses (partially to fully immunised). Older children may be best targeted through school-based programmes. A formal evaluation element should be incorporated into future catch-up campaigns to inform their continuing improvement.     

Mitogen-activated protein kinase phosphatase 2, MKP-2, regulates early inflammation in acute lung injury

Acute lung injury (ALI) is mediated by an early proinflammatory response resulting from either a direct or indirect insult to the lung mediating neutrophil infiltration and consequent disruption of the alveolar capillary membrane ultimately leading to refractory hypoxemia. The mitogen-activated protein kinase (MAPK) pathways are a key component of the molecular response activated by those insults triggering the proinflammatory response in ALI. The MAPK pathways are counterbalanced by a set of dual-specific phosphatases (DUSP) that deactivate the kinases by removing phosphate groups from tyrosine or threonine residues. We have previously shown that one DUSP, MKP-2, regulates the MAPK pathway in a model of sepsis-induced inflammation; however, the role of MKP-2 in modulating the inflammatory response in ALI has not been previously investigated. We utilized both MKP-2-null (MKP-2(-/-)) mice and MKP-2 knockdown in a murine macrophage cell line to elucidate the role of MKP-2 in regulating inflammation during ALI. Our data demonstrated attenuated proinflammatory cytokine production as well as decreased neutrophil infiltration in the lungs of MKP-2(-/-) mice following direct, intratracheal LPS. Importantly, when challenged with a viable pathogen, this decrease in neutrophil infiltration did not impact the ability of MKP-2(-/-) mice to clear either gram-positive or gram-negative bacteria. Furthermore, MKP-2 knockdown led to an attenuated proinflammatory response and was associated with an increase in phosphorylation of ERK and induction of a related DUSP, MKP-1. These data suggest that altering MKP-2 activity may have therapeutic potential to reduce lung inflammation in ALI without impacting pathogen clearance.     

The faint promise of a distant market: a survey of Belém's trade in non-timber forest products

Increased trade in non-timber forest products (NTFPs) has been promoted as one possible means to slow tropical deforestation by increasing the economic value of intact forest. A market survey of NTFPs occurring in the Capim River basin in eastern Amazonia, Brazil demonstrated that the reality for many smallholder communities in frontier and remote regions includes chronic transportation difficulties, high variability in fruit production, perishable products and lack of market expertise. In some communities, declining abundance of NTFPs due to logging and fire has resulted in a lack of forest products to even meet subsistence needs. In areas close to cities where transportation is assured and where forest clearing has eroded the natural occurrence of some valuable native NTFPs, smallholders who manage and successfully market native fruit and medicinal species are overcoming these obstacles. In frontier regions undergoing rapid transformation, however, decline in locally used and regionally marketed NTFPs currently pose detrimental consequences for communities. Findings suggest that an overemphasis on NTFP marketing has diverted attention from local livelihood, resource access and subsistence issues.     

Climate Change Sensitivity Index for Pacific Salmon Habitat in Southeast Alaska

Global climate change may become one of the most pressing challenges to Pacific Salmon conservation and management for southeast Alaska in the 21^st Century. Predicted hydrologic change associated with climate change will likely challenge the ability of specific stocks to adapt to new flow regimes and resulting shifts in spawning and rearing habitats. Current research suggests egg-to-fry survival may be one of the most important freshwater limiting factors in Pacific Salmon''s northern range due to more frequent flooding events predicted to scour eggs from mobile spawning substrates. A watershed-scale hydroclimatic sensitivity index was developed to map this hypothesis with an historical stream gauge station dataset and monthly multiple regression-based discharge models. The relative change from present to future watershed conditions predicted for the spawning and incubation period (September to March) was quantified using an ensemble global climate model average (ECHAM5, HadCM3, and CGCM3.1) and three global greenhouse gas emission scenarios (B1, A1B, and A2) projected to the year 2080. The models showed the region''s diverse physiography and climatology resulted in a relatively predictable pattern of change: northern mainland and steeper, snow-fed mountainous watersheds exhibited the greatest increases in discharge, an earlier spring melt, and a transition into rain-fed hydrologic patterns. Predicted streamflow increases for all watersheds ranged from approximately 1-fold to 3-fold for the spawning and incubation period, with increased peak flows in the spring and fall. The hydroclimatic sensitivity index was then combined with an index of currently mapped salmon habitat and species diversity to develop a research and conservation priority matrix, highlighting potentially vulnerable to resilient high-value watersheds. The resulting matrix and observed trends are put forth as a framework to prioritize long-term monitoring plans, mitigation experiments, and finer-scale climate impact and adaptation studies.     

Bridging the Gap: How Can Information Access and Exchange Between Conservation Biologists and Field Practitioners be Improved for Better Conservation Outcomes?

It is widely accepted that there is a considerable gap between the science of conservation biology and the design and execution of biodiversity conservation projects in the field and science is failing to inform the practice of conservation. There are many reasons why this implementation gap exists. A high proportion of papers published in scientific journals by conservation biologists are seldom read outside of the academic world and there are few incentives for academics to convert their science into practice. In turn, field practitioners rarely document their field experiences and experiments in a manner that can meaningfully inform conservation scientists. Issues related to access to scientific literature, scientific relevance in multidisciplinary environments, donor expectations and a lack of critical analysis at all levels of conservation theory and practice are factors that exacerbate the divide. The contexts in which conservation biologists and field practitioners operate are also often highly dissimilar, and each has differing professional responsibilities and expectations that compromise the ability to learn from each other's expertise. Building on recent debate in the literature, and using case studies to illustrate the issues that characterize the divide, this paper draws on the authors' experiences of project management as well as academic research. We identify five key issues related to information exchange: access to scientific literature, levels of scientific literacy, lack of interdisciplinarity, questions of relevance and lack of sharing of conservation-related experiences and suggest new ways of working that could assist in bridging the gap between conservation scientists and field practitioners.     

Towards an understanding of semaphorin signalling in the spinal cord

Semaphorins are a large family of proteins that are classically associated with axon guidance. These proteins and their interacting partners, the neuropilins and plexins are now known to be key mediators in a variety of processes throughout the nervous system ranging from synaptic refinement to the correct positioning of neuronal and glial cell bodies. Recently, much attention has been given to the roles semaphorins play in other body tissues including the immune and vascular systems. This review wishes to draw attention back to the nervous system, specifically focusing on the role of semaphorins in the development of the spinal cord and their proposed roles in the adult. In addition, their functions in spinal cord injury at the glial scar are also discussed.