Phagocytosis of Streptococcus pyogenes by all-trans retinoic acid-differentiated HL-60 cells: roles of azurophilic granules and NADPH oxidase.

BACKGROUND: New experimental approaches to the study of the neutrophil phagosome and bacterial killing prompted a reassessment of the usefulness of all-trans retinoic acid (ATRA)-differentiated HL-60 cells as a neutrophil model. HL-60 cells are special in that they possess azurophilic granules while lacking the specific granules with their associated oxidase components. The resulting inability to mount an effective intracellular respiratory burst makes these cells more dependent on other mechanisms when killing internalized bacteria. METHODOLOGY/PRINCIPAL FINDINGS: In this work phagocytosis and phagosome-related responses of ATRA-differentiated HL-60 cells were compared to those earlier described in human neutrophils. We show that intracellular survival of wild-type S. pyogenes bacteria in HL-60 cells is accompanied by inhibition of azurophilic granule-phagosome fusion. A mutant S. pyogenes bacterium, deficient in M-protein expression, is, on the other hand, rapidly killed in phagosomes that avidly fuse with azurophilic granules. CONCLUSIONS/SIGNIFICANCE: The current data extend our previous findings by showing that a system lacking in oxidase involvement also indicates a link between inhibition of azurophilic granule fusion and the intraphagosomal fate of S. pyogenes bacteria. We propose that differentiated HL-60 cells can be a useful tool to study certain aspects of neutrophil phagosome maturation, such as azurophilic granule fusion

Consumerisation in UK Higher Education Business Schools: Higher fees, greater stress and debatable outcomes

For many UK Higher Education Business Schools, the continued recruitment of UK, EU and International students is crucial for financial stability, viability and independence. Due to increasingly competitive funding models across the sector many institutional leaders and administrators are making decisions typical of highly marketised consumer environments. Thus, this paper explores, academics’ perceptions of the impact of consumerisation in UK Higher Education Business Schools. To achieve this 22 Business School academics were interviewed within three UK Higher Education institutions (HEIs) in the North of England. Participants had a minimum of three years teaching experience. Data was analysed using template analysis taking an interpretive approach. The findings indicate that academics perceived the introduction of tuition fees to have been the catalyst for students increasing demonstration of customer-like behaviour: viewing the education process as transactional, with the HEI providing a ‘paid for’ service. It is argued that these changes in UK Higher Education have created tensions between university leaders and academics, creating genuine dilemmas for those with decision-making responsibilities who must balance academic integrity and long term institutional financial viability

Functional characterization of the complement receptor type 1 and its circulating ligands in patients with schizophrenia

<p>Abstract</p> <p>Background</p> <p>Whereas the complement system alterations contribute to schizophrenia, complement receptors and regulators are little studied. We investigated complement receptor type 1 (CR1) expression on blood cells, the levels of circulating immune complexes (CIC) containing ligands of CR1, C1q complement protein and fragments of C3 complement protein (C1q-CIC, C3d-CIC), and CR1 C5507G functional polymorphism in schizophrenia patients and controls.</p> <p>Results</p> <p>We found an increased C1q-CIC level and CR1 expression on blood cells, elevated number of CR1 positive erythrocytes and reduced number of CR1 positive lymphocytes and monocytes in patients compared to controls. No difference in the levels of C3d-CIC between groups was observed. Higher CR1 expression on erythrocytes in CC genotype versus CG+GG for both groups was detected, whereas no difference was observed for other cell populations. Our results indicated that schizophrenia is associated with the increased CR1 expression and C1q-CIC level.</p> <p>Conclusions</p> <p>Our study for the first time indicated that schizophrenia is associated with the increased CR1 expression and C1q-CIC level. Further studies in other ethnic groups are needed to replicate these findings.</p

AKR1C enzymes sustain therapy resistance in paediatric T-ALL

BACKGROUND: Despite chemotherapy intensification, a subgroup of high-risk paediatric T-cell acute lymphoblastic leukemia (TALL) patients still experience treatment failure. In this context, we hypothesised that therapy resistance in T-ALL might involve aldo-keto reductase 1C (AKR1C) enzymes as previously reported for solid tumors.METHODS: Expression of NRF2-AKR1C signaling components has been analysed in paediatric T-ALL samples endowed with different treatment outcomes as well as in patient-derived xenografts of T-ALL. The effects of AKR1C enzyme modulation has been investigated in T-ALL cell lines and primary cultures by combining AKR1C inhibition, overexpression, and gene silencing approaches.RESULTS: We show that T-ALL cells overexpress AKR1C1-3 enzymes in therapy-resistant patients. We report that AKR1C1-3 enzymes play a role in the response to vincristine (VCR) treatment, also ex vivo in patient-derived xenografts. Moreover, we demonstrate that the modulation of AKR1C1-3 levels is sufficient to sensitise T-ALL cells to VCR. Finally, we show that T-ALL chemotherapeutics induce overactivation of AKR1C enzymes independent of therapy resistance, thus establishing a potential resistance loop during T-ALL combination treatment.CONCLUSIONS: Here, we demonstrate that expression and activity of AKR1C enzymes correlate with response to chemotherapeutics in T-ALL, posing AKR1C1-3 as potential targets for combination treatments during T-ALL therapy

Spatial navigation deficits — overlooked cognitive marker for preclinical Alzheimer disease?

Detection of incipient Alzheimer disease (AD) pathophysiology is critical to identify preclinical individuals and target potentially disease-modifying therapies towards them. Current neuroimaging and biomarker research is strongly focused in this direction, with the aim of establishing AD fingerprints to identify individuals at high risk of developing this disease. By contrast, cognitive fingerprints for incipient AD are virtually non-existent as diagnostics and outcomes measures are still focused on episodic memory deficits as the gold standard for AD, despite their low sensitivity and specificity for identifying at-risk individuals. This Review highlights a novel feature of cognitive evaluation for incipient AD by focusing on spatial navigation and orientation deficits, which are increasingly shown to be present in at-risk individuals. Importantly, the navigation system in the brain overlaps substantially with the regions affected by AD in both animal models and humans. Notably, spatial navigation has fewer verbal, cultural and educational biases than current cognitive tests and could enable a more uniform, global approach towards cognitive fingerprints of AD and better cognitive treatment outcome measures in future multicentre trials. The current Review appraises the available evidence for spatial navigation and/or orientation deficits in preclinical, prodromal and confirmed AD and identifies research gaps and future research priorities

Pegylated interferon-alpha-2b reduces corticosteroid requirement in patients with Behcet's disease with upregulation of circulating regulatory T cells and reduction of Th17

Objective To determine whether the addition of 26 weeks of subcutaneous peginterferon-α-2b could reduce the requirement for systemic corticosteroids and conventional immunosuppressive medication in patients with Behçet's disease (BD). Methods We conducted a multicentre randomised trial in patients with BD requiring systemic therapy. Patients were randomised to 26 weeks of peginterferon-α-2b in addition to their standard care or to standard care only and followed 6-monthly for 3 years with BD activity scores and quality of life questionnaires. Patients at one centre had blood taken to measure regulatory T cells (Tregs) and Th17 cells. Results 72 patients were included. At months 10–12, while among the entire patient population there was no difference in the corticosteroid dose or immunosuppression use between the treatment groups (adjusted OR 1.04, 95% CI 0.34 to 3.19), post hoc analysis revealed that in patients who were on corticosteroids at baseline the corticosteroid requirement was significantly lower in the peginterferon-α-2b (6.5 (5–15) mg/day) compared with the non-interferon group (10 (8.25–16.5) mg/day, p=0.039). Furthermore, there was a trend towards an improved quality of life that became significant by 36 months (p=0.008). This was associated with a significant rise in Tregs and a decrease in Th17 cells which was still present at 1 year and 6 months after the interferon was stopped. The safety profile was similar with adverse events in 10% in both groups. Conclusions The addition of peginterferon-α-2b to the drug regime of BD patients did not significantly reduce their corticosteroid dose required at 1 year. However, in those on corticosteroids at baseline post hoc analysis demonstrated that the addition of peginterferon-α-2b did result in a significant reduction in corticosteroid dose with a significantly improved quality of life and trend to reduce other required immunosuppressive agents. This effect was seen at 1 year and associated with a rise in Tregs suggesting a possible mode for interferon action. Trial registration number ISRCTN 36354474; EudraCT 2004-004301-18

Pegylated interferon-α-2b reduces corticosteroid requirement in patients with Behcet's disease with upregulation of circulating regulatory T cells and reduction of Th17.

OBJECTIVE: To determine whether the addition of 26 weeks of subcutaneous peginterferon-α-2b could reduce the requirement for systemic corticosteroids and conventional immunosuppressive medication in patients with Behçet's disease (BD). METHODS: We conducted a multicentre randomised trial in patients with BD requiring systemic therapy. Patients were randomised to 26 weeks of peginterferon-α-2b in addition to their standard care or to standard care only and followed 6-monthly for 3 years with BD activity scores and quality of life questionnaires. Patients at one centre had blood taken to measure regulatory T cells (Tregs) and Th17 cells. RESULTS: 72 patients were included. At months 10-12, while among the entire patient population there was no difference in the corticosteroid dose or immunosuppression use between the treatment groups (adjusted OR 1.04, 95% CI 0.34 to 3.19), post hoc analysis revealed that in patients who were on corticosteroids at baseline the corticosteroid requirement was significantly lower in the peginterferon-α-2b (6.5 (5-15) mg/day) compared with the non-interferon group (10 (8.25-16.5) mg/day, p=0.039). Furthermore, there was a trend towards an improved quality of life that became significant by 36 months (p=0.008). This was associated with a significant rise in Tregs and a decrease in Th17 cells which was still present at 1 year and 6 months after the interferon was stopped. The safety profile was similar with adverse events in 10% in both groups. CONCLUSIONS: The addition of peginterferon-α-2b to the drug regime of BD patients did not significantly reduce their corticosteroid dose required at 1 year. However, in those on corticosteroids at baseline post hoc analysis demonstrated that the addition of peginterferon-α-2b did result in a significant reduction in corticosteroid dose with a significantly improved quality of life and trend to reduce other required immunosuppressive agents. This effect was seen at 1 year and associated with a rise in Tregs suggesting a possible mode for interferon action. TRIAL REGISTRATION NUMBER: ISRCTN 36354474; EudraCT 2004-004301-18