Cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine

Defective efferocytosis may perpetuate inflammation in smokers with or without chronic obstructive pulmonary disease (COPD). Macrophages may phenotypically polarize to classically activated M1 (proinflammatory; regulation of antigen presentation) or alternatively activated M2 (poor antigen presentation; improved efferocytosis) markers. In bronchoalveolar lavage (BAL)–derived macrophages from control subjects and smoker/ex-smoker COPD subjects, we investigated M1 markers (antigen-presenting major histocompatibility complex [MHC] Classes I and II), complement receptors (CRs), the high-affinity Fc receptor involved with immunoglobulin binding for phagocytosis (Fc-gamma receptor, FcγR1), M2 markers (dendritic cell–specific intercellular adhesion molecule-grabbing nonintegrin [DC-SIGN] and arginase), and macrophage function (efferocytosis and proinflammatory cytokine production in response to LPS). The availability of glutathione (GSH) in BAL was assessed, because GSH is essential for both M1 function and efferocytosis. We used a murine model to investigate macrophage phenotype/function further in response to cigarette smoke. In lung tissue (disaggregated) and BAL, we investigated CRs, the available GSH, arginase, and efferocytosis. We further investigated the therapeutic effects of an oral administration of a GSH precursor, cysteine l-2-oxothiazolidine-4-carboxylic acid (procysteine). Significantly decreased efferocytosis, available GSH, and M1 antigen–presenting molecules were evident in both COPD groups, with increased DC-SIGN and production of proinflammatory cytokines. Increased CR-3 was evident in the current-smoker COPD group. In smoke-exposed mice, we found decreased efferocytosis (BAL and tissue) and available GSH, and increased arginase, CR-3, and CR-4. Treatment with procysteine significantly increased GSH, efferocytosis (BAL: control group, 26.2%; smoke-exposed group, 17.66%; procysteine + smoke-exposed group, 27.8%; tissue: control group, 35.9%; smoke-exposed group, 21.6%; procysteine + smoke-exposed group, 34.5%), and decreased CR-4 in lung tissue. Macrophages in COPD are of a mixed phenotype and function. The increased efferocytosis and availability of GSH in response to procysteine indicates that this treatment may be useful as adjunct therapy for improving macrophage function in COPD and in susceptible smokers.

Systemic activation of dendritic cells by toll-like receptor ligands or malaria infection impairs cross-presentation and antiviral immunity

The mechanisms responsible for the immunosuppression associated with sepsis or some chronic blood infections remain poorly understood. Here we show that infection with a malaria parasite (Plasmodium berghei) or simple systemic exposure to bacterial or viral Toll-like receptor ligands inhibited cross-priming. Reduced cross-priming was a consequence of downregulation of cross-presentation by activated dendritic cells due to systemic activation that did not otherwise globally inhibit T cell proliferation. Although activated dendritic cells retained their capacity to present viral antigens via the endogenous major histocompatibility complex class I processing pathway, antiviral responses were greatly impaired in mice exposed to Toll-like receptor ligands. This is consistent with a key function for cross-presentation in antiviral immunity and helps explain the immunosuppressive effects of systemic infection. Moreover, inhibition of cross-presentation was overcome by injection of dendritic cells bearing antigen, which provides a new strategy for generating immunity during immunosuppressive blood infections.

Order of question presentation and correlation between judgments of comparative and own risk

Unrealistic optimism is often assessed using a single question asking for an estimate of comparative risk. However, it has been proposed that individuals treat such a question essentially as though it were only about their own risk. This proposal leads to the prediction that, when the questions about own risk and comparative risk are asked in sequence, the correlation between the resulting estimates should be lower if the question about own risk comes first than if the question about comparative risk comes first. This prediction was tested using a student sample (N=68). Participants answered the two types of question in sequence, with order of presentation being counterbalanced. Results were in accord with the prediction. Possible reasons are advanced for individuals' answering questions about comparative risk as if the questions concerned their own risk.

Triangulation in organizational research : a re-presentation

This paper extends the discussion of postmodern thinking in organizational theory through a re-presentation of the concept of triangulation in organizational research. Initially triangulation is defined through the contrasting lenses of positivism and post-positivism/postmodernism and analysed as a metaphor for fixing and capturing the research subject. Subsequently triangulation is ‘re-presented’ as ‘metaphorization’—in terms of process and movement between researcher-subject positions. Rethinking the lines and angles of enquiry in triangulation, the paper suggests a shift from the ‘triangulation of distance’ tradition to a more reflexive consideration of ‘researcher stance’. This movement is represented across three perspectives: the researcher as a follower of nomothetic lines; the researcher as the taker of an ideographic overview; and the researcher as the finder of a particular angle. The implications of this re-presentation are then discussed in terms of perspective, data capture, reflexivity and metatriangulation.

The roles of prior experience and the timing of misinformation presentation on young children's event memories

The current study addressed how the timing of interviews affected children's memories of unique and repeated events. Five- to six-year-olds (N= 125) participated in activities 1 or 4 times and were misinformed either 3 or 21 days after the only or last event. Although single-experience children were subsequently less accurate in the 21- versus 3-day condition, the timing of the misinformation session did not affect memories of repeated-experience children regarding invariant details. Children were more suggestible in the 21- versus 3-day condition for variable details when the test occurred soon after misinformation presentation. Thus, timing differentially affected memories of single and repeated events and depended on the combination of event-misinformation and misinformation-test delays rather than the overall retention interval.

Evidence for a common role for the serine-type Plasmodium falciparum serine repeat antigen proteases : implications for vaccine and drug design

Serine repeat antigens (SERAs) are a family of secreted “cysteine-like” proteases of Plasmodium parasites. Several SERAs possess an atypical active-site serine residue in place of the canonical cysteine. The human malaria parasite Plasmodium falciparum possesses six “serine-type” (SERA1 to SERA5 and SERA9) and three “cysteine-type” (SERA6 to SERA8) SERAs. Here, we investigate the importance of the serine-type SERAs to blood-stage parasite development and examine the extent of functional redundancy among this group. We attempted to knock out the four P. falciparum serine-type SERA genes that have not been disrupted previously. SERA1, SERA4, and SERA9 knockout lines were generated, while only SERA5, the most strongly expressed member of the SERA family, remained refractory to genetic deletion. Interestingly, we discovered that while SERA4-null parasites completed the blood-stage cycle normally, they exhibited a twofold increase in the level of SERA5 mRNA. The inability to disrupt SERA5 and the apparent compensatory increase in SERA5 expression in response to the deletion of SERA4 provides evidence for an important blood-stage function for the serine-type SERAs and supports the notion of functional redundancy among this group. Such redundancy is consistent with our phylogenetic analysis, which reveals a monophyletic grouping of the serine-type SERAs across the genus Plasmodium and a predominance of postspeciation expansion. While SERA5 is to some extent further validated as a target for vaccine and drug development, our data suggest that the expression level of other serine-type SERAs is the only barrier to escape from anti-SERA5-specific interventions.

Is tendon pathology a continuum? A pathology model to explain the clinical presentation of load-induced tendinopathy

Overuse tendinopathy is problematic to manage clinically. People of different ages with tendons under diverse loads present with varying degrees of pain, irritability, and capacity to function. Recovery is similarly variable; some tendons recover with simple interventions, some remain resistant to all treatments.

The pathology of tendinopathy has been described as degenerative or failed healing. Neither of these descriptions fully explains the heterogeneity of presentation. This review proposes, and provides evidence for, a continuum of pathology. This model of pathology allows rational placement of treatments along the continuum.

A new model of tendinopathy and thoughtful treatment implementation may improve outcomes for those with tendinopathy. This model is presented for evaluation by clinicians and researchers.

Simultaneous presentation of measured and calculated environmental results

Continuous measurement of internal and external environmental parameters is critical to our understanding of how buildings perform. Yet, the quantity and variety of time-series data can be quite overwhelming as well as onerous to decipher and present. In addition to this, is the fact that several of the collected data are useless in their raw format unless processed through algorithms to obtain identifiable and meaningful results.
These circumstances challenge the conventional way we present accumulated data and their processed outputs in order to get a better understanding of how and why the environmental performance occurred. It would be ideal if all of the collected and processed data could be presented in a simultaneous, yet, useful format. It is exactly the intention of this paper to suggest and present such a process as well as its format.
An example case study is provided where several parameters (air velocity, mean radiant temperature, humidity and air temperature) are measured periodically to calculate a time-series of internal comfort performance. However, external conditions of solar radiation and solar position as well as air temperature drive the interior building surface temperatures and help to explain the end result of internal comfort.
A program has been written to present the various sets of data graphically, in an integrated manner, animated as a function of time. The animation shows solar position, a cursor scanning weather data, the changing infra-red image and a representation of the resulting internal comfort performance throughout the
monitored period.