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Mosquitoes are the most important vectors for arthropod-borne viral diseases. Mixed viral infections of mosquitoes allow genetic recombination or reassortment of diverse viruses, turning mosquitoes into potential virologic mixing bowls. In this study, we field-collected mosquitoes of different species (Aedes aegypti and Culex pipiens complex), from different geographic locations and environments (central Europe and the Caribbean) for highly sensitive next-generation sequencing-based virome characterization. We found a rich virus community associated with a great diversity of host species. Among those, we detected a large diversity of novel virus sequences that we could predominately assign to circular Rep-encoding single-stranded (CRESS) DNA viruses, including the full-length genome of a yet undescribed Gemykrogvirus species. Moreover, we report for the first time the detection of a potentially zoonotic CRESS-DNA virus (Cyclovirus VN) in mosquito vectors. This study expands the knowledge on virus diversity in medically important mosquito vectors, especially for CRESS-DNA viruses that have previously been shown to easily recombine and jump the species barrier.

Cantharidin skin blisters were examined over two days to model the acute and resolving phases of inflammation in human skin. Four blisters were created by topical administration of cantharidin (0.1% v/v) to the forearm of healthy volunteers, with IRB approval. Duplicate skin blisters were aspirated at 16 and 40 hours to model the proinflammatory and resolving phases, respectively. There was a significant increase in leukocyte infiltrate at 40 h with appearance of a “resolving macrophage” phenotype CD14+CD163+ by flow cytometry. Neutrophils acquired apoptotic markers at 40 h and were observed to be phagocytosed by macrophagic “Reiter’s” cells. Multiplex cytokine analysis demonstrated that monocyte chemoattractant protein (MCP-1/CCL2), interleukin- (IL-) 6, IL-8/CXCL8, macrophage inflammatory protein (MIP1α/CCL3), MIP-1β/CCL4, tumor necrosis factor- (TNF-) α, and eotaxin (CCL11) were all significantly upregulated at 16 h compared with 40 h. In contrast, immunoregulatory transforming growth factor- (TGF-) β, macrophage-derived chemokine (MDC/CCL22), and interferon-inducible protein (IP-10/CXCL10) were significantly elevated at 40 h. Our results demonstrate that the phases of inflammation and resolution can be discriminated in a two-day model of dermal wound healing. This confirms and extends our understanding of wound repair in humans and provides a powerful research tool for use in clinical settings and to track the molecular benefits of therapeutic intervention.

Intraplaque hemorrhage causes adaptive remodelling of macrophages towards a protective phenotype specialized towards handling iron and lipid overload, denoted Mhem. The Mhem phenotype expresses elevated levels of hemoglobin (Hb) scavenger receptor, CD163, capable of endocytosing pro-oxidant free Hb complexed to acute phase protein haptoglobin (Hp). It is notable that individuals homozygous for the Hp 2 allele (a poorer antioxidant) are at increased risk of cardiovascular disease compared to the Hp 1 allele. In this study, we examined whether scavenging of polymorphic Hp:Hb complexes differentially generated downstream anti-inflammatory signals in cultured human macrophages culminating in interleukin (IL)-10 secretion. We describe an anti-inflammatory signalling pathway involving phosphatidylinositol-3-kinase activation upstream of Akt phosphorylation (pSer473Akt) and IL-10 secretion. The pathway is mediated specifically through CD163 and is blocked by anti-CD163 antibody or phagocytosis inhibitor. However, levels of pSer473Akt and IL-10 were significantly diminished when scavenging polymorphic Hp2-2:Hb complexes compared to Hp1-1:Hb complexes (P<0.05). Impaired anti-inflammatory macrophage signaling through a CD163/pAkt/IL-10 axis may thus represent a possible Hp2-2 disease mechanism in atherosclerosis.

Approximately 1 in 5 patients undergoing cardiac surgery are readmitted within 30 days of discharge. Among the primary causes of readmission are infection and disease states susceptible to the inflammatory cascade, such as diabetes, chronic obstructive pulmonary disease, and gastrointestinal complications. Currently, it is not known if a patient’s baseline inflammatory state measured by crude white blood cell (WBC) counts could predict 30-day readmission. We collected data from 2,176 consecutive patients who underwent cardiac surgery at seven hospitals. Patient readmission data was abstracted from each hospital. The independent association with preoperative WBC count was determined using logistic regression. There were 259 patients readmitted within 30 days, with a median time of readmission of 9 days (IQR 4–16). Patients with elevated WBC count at baseline (10,000–12,000 and >12,000 mm3) had higher 30-day readmission than those with lower levels of WBC count prior to surgery (15% and 18% compared to 10%–12%, P=0.037). Adjusted odds ratios were 1.42 (0.86, 2.34) for WBC counts 10,000–12,000 and 1.81 (1.03, 3.17) for WBC count > 12,000. We conclude that WBC count measured prior to cardiac surgery as a measure of the patient’s inflammatory state could aid clinicians and continuity of care management teams in identifying patients at heightened risk of 30-day readmission after discharge from cardiac surgery.

In Barbados, use of the Systemic Lupus Erythematosus (SLE) Disease Activity Index (SLEDAI) is limited by the unavailability of serologic markers. The SLE Activity Questionnaire (SLAQ) excludes laboratory measurements and is therefore more accessible. Here, we investigate the agreement between the SLAQ, the SLEDAI, and the physician global assessment (PGA). A pilot of 32 participants completed the SLAQ and SLEDAI. The tools were compared (1) in their original format, (2) limited to common indices, and (3) limited to the same patient recall period. We compared the proportions of persons reporting disease activity and the concordance between calculated activity scores for SLAQ versus SLEDAI and for SLAQ versus PGA. Seventy-eight percent versus 59% of participants reported disease activity with the original SLEDAI versus SLAQ, respectively. The relationship was reversed to 22% versus 59% when the matched item tools were compared. Concordance was 0.62 (95% CI 0.42–0.81) between the original scores, 0.70 (0.57–0.83) when restricted by matched items, and 0.72 (0.59–0.84) when further restricted by recall period. Concordance between the SLAQ and PGA was 0.56 (0.32–0.80). Reversal of the disease activity percentage in the matched items comparison highlights the inadequacy of tools that exclude laboratory measurements and suggests that the subjective nature of SLAQ may contribute to over-reporting. Further work is needed to produce a robust disease activity tool apt for resource-constrained environments.

The objective of this study was to determine whether plasmin could induce morphological changes in human glial cells via PAR1. Human glioblastoma A172 cells were cultured in the presence of plasmin or the PAR1 specific activating hexapeptide, SFLLRN. Cells were monitored by flow cytometry to detect proteolytic activation of PAR1 receptor. Morphological changes were recorded by photomicroscopy and apoptosis was measured by annexinV staining. Plasmin cleaved the PAR1 receptor on glial cells at 5 minutes (P=0.02). After 30 minutes, cellular processes had begun to retract from the basal substratum and by 4 hours glial cells had become detached. Similar results were obtained by generating plasmin de novo from plasminogen. Morphological transformation was blocked by plasmin inhibitors aprotinin or epsilon-aminocaproic acid (P=0.03). Cell viability was unimpaired during early morphological changes, but by 24 hours following plasmin treatment 22% of glial cells were apoptotic. PAR1 activating peptide SFLLRN (but not inactive isomer FSLLRN) promoted analogous glial cell detachment (P=0.03), proving the role for PAR1 in this process. This study has identified a plasmin/PAR1 axis of glial cell activation, linked to changes in glial cell morophology. This adds to our understanding of pathophysiological disease mechanisms of plasmin and the plasminogen system in neuroinjury.

[...]an original paper compared the immunosuppressive properties of statins on T-cell immune responses with other conventional immunosuppressive agents, such as cyclosporine or dexamethasone (A. Jameel et al.). The paper demonstrated differential immunosuppressive properties of statins on T-cell proliferation, IL-1β, IL-17, and interferon- (IFN-) γ production depending on the type of immune activation. 4. CD163+ cells were associated in the second paper with the phagocytic removal of apoptotic neutrophils, hence limiting potential histotoxic injury, with a shifting of the cytokine profile from proinflammatory mediators, including TNF-α, IL-6, IL-8/CXCL8, monocyte chemoattractant protein (MCP-1/CCL2), macrophage inflammatory protein (MIP1α/CCL3), MIP-1β/CCL4, and eotaxin (CCL11), towards immunoregulatory mediators, including macrophage-derived chemokine (MDC/CCL22), interferon-inducible protein (IP-10/CXCL10), and transforming growth factor (TGF)-β. [...]an interesting review of proresolving mediators highlights the promise of melanocortin peptides as agents to limit the inflammatory process and protect tissues in a variety of preclinical models for inflammatory disease. 5.